Imidazopyrazines

ABSTRACT

The present invention relates to imidazopyrazine compounds of general Formula (I): in which X, R 1 , R 2 , R 3a , R 3b , R 4a , R 4b , R 4C , and R 4D  are as given in the description and in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.

The present invention relates to imidazopyrazine compounds of generalformula (I) as described and defined herein, to methods of preparingsaid compounds, to pharmaceutical compositions and combinationscomprising said compounds, to the use of said compounds formanufacturing a pharmaceutical composition for the treatment orprophylaxis of a disease, as well as to intermediate compounds useful inthe preparation of said compounds.

BACKGROUND OF THE INVENTION

The present invention relates to chemical compounds that inhibit Mps-1(Monopolar Spindle 1) kinase (also known as Tyrosine Threonine Kinase,TTK). Mps-1 is a dual specificity Ser/Thr kinase which plays a key rolein the activation of the mitotic checkpoint (also known as spindlecheckpoint, spindle assembly checkpoint) thereby ensuring properchromosome segregation during mitosis [Abrieu A et al., Cell, 2001, 106,83-93]. Every dividing cell has to ensure equal separation of thereplicated chromosomes into the two daughter cells. Upon entry intomitosis, chromosomes are attached at their kinetochores to themicrotubules of the spindle apparatus. The mitotic checkpoint is asurveillance mechanism that is active as long as unattached kinetochoresare present and prevents mitotic cells from entering anaphase andthereby completing cell division with unattached chromosomes[Suijkerbuijk S J and Kops G J, Biochemica et Biophysica Acta, 2008,1786, 24-31; Musacchio A and Salmon E D, Nat Rev Mol Cell Biol., 2007,8, 379-93]. Once all kinetochores are attached in a correct amphitelic,i.e. bipolar, fashion with the mitotic spindle, the checkpoint issatisfied and the cell enters anaphase and proceeds through mitosis. Themitotic checkpoint consists of complex network of a number of essentialproteins, including members of the MAD (mitotic arrest deficient, MAD1-3) and Bub (Budding uninhibited by benzimidazole, Bub 1-3) families,the motor protein CENP-E, Mps-1 kinase as well as other components, manyof these being over-expressed in proliferating cells (e.g. cancer cells)and tissues [Yuan B et al., Clinical Cancer Research, 2006, 12, 405-10].The essential role of Mps-1 kinase activity in mitotic checkpointsignalling has been shown by shRNA-silencing, chemical genetics as wellas chemical inhibitors of Mps-1 kinase [Jelluma N et al., PLos ONE,2008, 3, e2415; Jones M H et al., Current Biology, 2005, 15, 160-65;Dorer R K et al., Current Biology, 2005, 15, 1070-76; Schmidt M et al.,EMBO Reports, 2005, 6, 866-72].

There is ample evidence linking reduced but incomplete mitoticcheckpoint function with aneuploidy and tumorigenesis [Weaver B A andCleveland D W, Cancer Research, 2007, 67, 10103-5; King R W, Biochimicaet Biophysica Acta, 2008, 1786, 4-14]. In contrast, complete inhibitionof the mitotic checkpoint has been recognised to result in severechromosome missegregation and induction of apoptosis in tumour cells[Kops G J et al., Nature Reviews Cancer, 2005, 5, 773-85; Schmidt M andMedema R H, Cell Cycle, 2006, 5, 159-63; Schmidt M and Bastians H, DrugResistance Updates, 2007, 10, 162-81]. Therefore, mitotic checkpointabrogation through pharmacological inhibition of Mps-1 kinase or othercomponents of the mitotic checkpoint represents a new approach for thetreatment of proliferative disorders including solid tumours such ascarcinomas and sarcomas and leukaemias and lymphoid malignancies orother disorders associated with uncontrolled cellular proliferation.

Established anti-mitotic drugs such as vinca alkaloids, taxanes orepothilones activate the SAC inducing a mitotic arrest either bystabilising or destabilising microtubule dynamics. This arrest preventsseparation of sister chromatids to form the two daughter cells.Prolonged arrest in mitosis forces a cell either into mitotic exitwithout cytokinesis or into mitotic catastrophe leading to cell death.

In contrast, inhibitors of Mps1 induce a SAC inactivation thataccelerates progression of cells through mitosis resulting in severechromosomal missegregation and finally in cell death.

These findings suggest that MPS1 inhibitors should be of therapeuticvalue for the treatment of proliferative disorders associated withenhanced uncontrolled proliferative cellular processes such as, forexample, cancer, inflammation, arthritis, viral diseases,neurodegenerative diseases such as Alzheimer's disease, cardiovasculardiseases, or fungal diseases in a warm-blooded animal such as man.

Therefore, inhibitors of MPS1 represent valuable compounds that shouldcomplement therapeutic options either as single agents or in combinationwith other drugs.

Protein kinase inhibitors based on substitutedimidazo[1,2-a]pyrazin-8-amine compounds are well known and are claimedto specifically inhibit CDK1, CDK2, MAPK, ERK, GSK3β, JNK, CHK-1, CHK-2,VEGF-R2, EGFR, HER2, SRC, JAK, TEK, Aurora, MK1, MK2, AKT, Pim-1, Abland Src kinases (see WO 2004/026877, US 2006/0106023, US 2007/0105864,WO 2007/058942, WO 2007/131991, WO2007/145921, WO 2008/079460, WO2008/057512, WO 2008/082490, WO 2009/097233, US 2009/0175852).

However, the state of the art described above does not describe theimidazopyrazine compounds of general formula (I) of the presentinvention, or a stereoisomer, a tautomer, an N-oxide, a hydrate, asolvate, or a salt thereof, or a mixture of same, as described anddefined herein, and as hereinafter referred to as “compounds of thepresent invention”, or their pharmacological activity. It has now beenfound, and this constitutes the basis of the present invention, thatsaid compounds of the present invention have surprising and advantageousproperties.

In particular, said compounds of the present invention have surprisinglybeen found to effectively inhibit Mps-1 kinase and may therefore be usedfor the treatment or prophylaxis of diseases of uncontrolled cellgrowth, proliferation and/or survival, inappropriate cellular immuneresponses, or inappropriate cellular inflammatory responses or diseaseswhich are accompanied with uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses, particularly in which theuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses is mediated by Mps-1 kinase, such as, for example,haemotological tumours, solid tumours, and/or metastases thereof, e.g.leukaemias and myelodysplastic syndrome, malignant lymphomas, head andneck tumours including brain tumours and brain metastases, tumours ofthe thorax including non-small cell and small cell lung tumours,gastrointestinal tumours, endocrine tumours, mammary and othergynaecological tumours, urological tumours including renal, bladder andprostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

DESCRIPTION OF THE INVENTION

In accordance with a first aspect, the present invention coverscompounds of general formula (I):

in which:

-   X represents an —SR⁵, —S(═O)R⁵, —S(═O)₂R⁵, —S(═O)(═NR^(5a))R^(5b),    or —S(═O)₂N(R^(5b))R^(5c) group;-   R¹ represents a hydrogen atom or a halogen atom, or a —CN,    C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-,    HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,    halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,    —C(═O)R⁸, —C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶,    —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b),    —N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),    —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸, —N(R^(8a))C(═O)OR^(8b),    —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸,    —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸, —O(C═O)R⁸,    —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,    —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸,    —S(═O)₂N(R^(8a))R^(8b), or —S(═O)(═NR^(8a))R^(8b) group-   R² represents a hydrogen atom or a halogen atom, or a —CN,    C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-,    HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,    halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₂-C₆-alkenyl-, or C₂-C₆-alkynyl-,    —C(═O)R⁸, —C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶,    —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b),    —N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),    —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸, —N(R^(8a))C(═O)OR^(8b),    —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸,    —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸, —O(C═O)R⁸,    —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,    —S(═O)N(R^(8a))R^(8b), —S(—O₂)R⁸, —S(═O)₂N(H)R⁸,    —S(═O)₂N(R^(8a))R^(8b), or —S(═O)(═NR^(8a))R^(8b) group;    -   or a group selected from:

-   -   (in which * indicates the point of attachment of said group with        the rest of the molecule);

-   R^(3a), R^(3b)    -   represent, independently from one another, a hydrogen atom or a        halogen atom, or a —CN, C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,        —(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl,        —(CH₂)_(m)-(3- to 7-membered heterocycloalkyl),        aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,        R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,        C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-,        C₃-C₆-cycloalkyl-, a 3- to 7-membered heterocycloalkyl,        C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-,        C₁-C₆-alkyl-aryl-, heteroaryl, —C(═O)R⁸, —C(═O)N(H)R⁸,        —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶, —N(R^(8a))R^(8b), —NO₂,        —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂,        —N(H)C(═O)N(H)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),        —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸,        —N(R^(8a))C(═O)OR^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),        —N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b),        —OH, —OR⁸, —O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸,        —S(═O)R⁸, —S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸,        —S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b), or —S(═O)(═NR^(8a))R^(8b)        group;    -   said C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,        —(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl,        aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a        3- to 7-membered heterocycloalkyl, C₂-C₆-alkenyl-,        C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-, C₁-C₆-alkyl-aryl-,        heteroaryl,    -   being optionally substituted, identically or differently, with        1, 2, 3, or 4 R⁷ groups;

-   R^(4a), R^(4b), R^(4c), R^(4d)    -   represent, independently from each other, a hydrogen or halogen        atom, or a —CN, halo-C₁-C₆-alkyl-, R^(8a)(R^(8b))N—C₁-C₆-alkyl-,        HO—C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl-,        halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, —C(═O)R⁸, —C(═O)N(H)R⁸,        —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁸, —N(R^(8a))R^(8b), —NO₂,        —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),        —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸,        —N(R^(8a))C(═O)OR^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),        —N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b),        —OH, —OR⁸, —O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸,        —S(═O)R⁸, —S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸,        —S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b), —S(═O)(═NR^(8a))R^(8b)        group;

-   or

-   R^(4c), together with R², forms an *N(R⁶)—N═C*—NH₂ group, (in    which * indicates the point of attachment of said group with the    rest of the molecule);

-   R⁵, R^(5b), R^(5c),    -   represent, independently from each other, a hydrogen atom, or a        C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,        —(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl,        —(CH₂)_(m)-(3- to 7-membered heterocycloalkyl),        aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,        R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,        C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-,        C₃-C₆-cycloalkyl-, a 3- to 7-membered heterocycloalkyl,        C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-,        heteroaryl group;    -   said C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,        —(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl,        —(CH₂)_(m)-(3- to 7-membered heterocycloalkyl),        aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,        R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,        C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-,        C₃-C₆-cycloalkyl-, a 3- to 7-membered heterocycloalkyl,        C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-,        heteroaryl,    -   being optionally substituted, identically or differently, with        1, 2, 3, or 4 R⁷ groups;

-   R^(5a) represents a hydrogen atom or a —C(═O)—C₁-C₆-alkyl, or    —C(═O)—C₃-C₆-cycloalkyl group; said C₁-C₆-alkyl being optionally    substituted, identically or differently, with one or more halogen    atom;

-   R⁶, R^(6a)    -   represent, independently from each other, a hydrogen atom or a        C₁-C₆-alkyl or C₃-C₆-cycloalkyl group,

-   R⁷ represents a hydrogen or halogen atom, or a —CN,    halo-C₁-C₆-alkyl-, R^(8a)(R^(8b))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl,    C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-,    C₂-C₆-alkenyl, —C(═O)R⁸, —C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b),    —C(═O)O—R⁸, —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸,    —N(R^(8a))C(═O)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),    —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸, —N(R^(8a))C(═O)OR^(8b),    —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸,    —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸, —O(C═O)R⁸,    —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,    —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸,    —S(═O)₂N(R^(8a))R^(8b), —S(═O)(═NR^(8a))R^(8b) group;

-   R⁸, R^(8a), R^(8b),    -   represent, independently from each other, a hydrogen atom, or a        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, 3- to 7-membered        heterocycloalkyl, aryl, heteroaryl, aryl-C₁-C₆-alkyl-, or        heteroaryl-C₁-C₆-alkyl- group;

-   m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;    or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

The terms as mentioned in the present text have preferably the followingmeanings:

The term “halogen atom” or “halo-” is to be understood as meaning afluorine, chlorine, bromine or iodine atom, preferably a fluorine,chlorine, bromine or iodine atom.

The term “C₁-C₆-alkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group having 1, 2,3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl,hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl,2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl,neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl,3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or anisomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms(“C₁-C₄-alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl,iso-butyl, sec-butyl, tert-butyl group, more particularly 1, 2 or 3carbon atoms (“C₁-C₃-alkyl”), e.g. a methyl, ethyl, n-propyl- oriso-propyl group.

The term “halo-C₁-C₆-alkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group in which theterm “C₁-C₆-alkyl” is defined supra, and in which one or more hydrogenatoms is replaced by a halogen atom, in identically or differently, i.e.one halogen atom being independent from another. Particularly, saidhalogen atom is F. Said halo-C₁-C₆-alkyl group is, for example, —CF₃,—CHF₂, —CH₂F, —CF₂CF₃, or —CH₂CF₃.

The term “C₁-C₆-alkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent, hydrocarbon group of formula—O-alkyl, in which the term “alkyl” is defined supra, e.g. a methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy,sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomerthereof.

The term “halo-C₁-C₆-alkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent C₁-C₆-alkoxy group, as definedsupra, in which one or more of the hydrogen atoms is replaced, inidentically or differently, by a halogen atom. Particularly, saidhalogen atom is F. Said halo-C₁-C₆-alkoxy group is, for example, —OCF₃,—OCHF₂, —OCH₂F, —OCF₂CF₃, or —OCH₂CF₃.

The term “C₁-C₆-alkoxy-C₁-C₆-alkyl” is to be understood as preferablymeaning a linear or branched, saturated, monovalent alkyl group, asdefined supra, in which one or more of the hydrogen atoms is replaced,in identically or differently, by a C₁-C₆-alkoxy group, as definedsupra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso-propoxyalkyl,butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl,pentyloxyalkyl, iso-pentyloxyalkyl, hexyloxyalkyl group, in which theterm “C₁-C₆-alkyl” is defined supra, or an isomer thereof.

The term “halo-C₁-C₆-alkoxy-C₁-C₆-alkyl” is to be understood aspreferably meaning a linear or branched, saturated, monovalentC₁-C₆-alkoxy-C₁-C₆-alkyl group, as defined supra, in which one or moreof the hydrogen atoms is replaced, in identically or differently, by ahalogen atom. Particularly, said halogen atom is F. Saidhalo-C₁-C₆-alkoxy-C₁-C₆-alkyl group is, for example, —CH₂CH₂OCF₃,—CH₂CH₂OCHF₂, —CH₂CH₂OCH₂F, —CH₂CH₂OCF₂CF₃, or —CH₂CH₂OCH₂CF₃.

The term “C₂-C₆-alkenyl” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group, which contains one ormore double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms,particularly 2 or 3 carbon atoms (“C₂-C₃-alkenyl”), it being understoodthat in the case in which said alkenyl group contains more than onedouble bond, then said double bonds may be isolated from, or conjugatedwith, each other. Said alkenyl group is, for example, a vinyl, allyl,(E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl,(Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl,(E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl,(E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl,(Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl,(Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl,2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl,(E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl,2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl,(E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl,(Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl,(E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl,(Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl,1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl,3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl,4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl,(E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl,(E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl,(E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl,(E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl,(E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl,(E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl,(E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl,(E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl,(E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl,(E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl,2-ethylbut-3-e nyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl,(Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl,(E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl,(Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl,(Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl,2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl,(Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl,(Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl,(Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl,(Z)-1-isopropylprop-1-enyl, (E)-3,3-dimethylprop-1-enyl,(Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl,buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienylgroup. Particularly, said group is vinyl or allyl.

The term “C₂-C₆-alkynyl” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group which contains one ormore triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms,particularly 2 or 3 carbon atoms (“C₂-C₃-alkynyl”). Said C₂-C₆-alkynylgroup is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl,but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl,pent-4-ynyl, hex-1-ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl,1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl,1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl,3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl,2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl,1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl,2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl,1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethyl-but-3-inyl,1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or3,3-dimethyl-but-1-ynyl group. Particularly, said alkynyl group isethynyl, prop-1-ynyl, or prop-2-inyl.

The term “C₃-C₆-cycloalkyl” is to be understood as preferably meaning asaturated, monovalent, mono-, or bicyclic hydrocarbon ring whichcontains 3, 4, 5 or 6 carbon atoms (“C₃-C₆-cycloalkyl”). SaidC₃-C₆-cycloalkyl group is for example, a monocyclic hydrocarbon ring,e.g. a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl or a bicyclichydrocarbon ring, e.g. a perhydropentalenylene or decalin ring. Saidcycloalkyl ring can optionally contain one or more double bonds e.g.cycloalkenyl, such as a cyclopropenyl, cyclobutenyl, cyclopentenyl orcyclohexenyl group, wherein the bond between said ring with the rest ofthe molecule may be to any carbon atom of said ring, be it saturated orunsaturated.

The term “heterocyclic ring”, as used in the term “4-, 5-, 6-, 7-, 8-,9- or 10-membered heterocyclic ring”, or “4- to 6-membered heterocyclicring” or “5- to 6-membered heterocyclic ring”, for example, as used inthe definition of compounds of general formula (I) as defined herein, isto be understood as meaning a saturated or partially unsaturated, mono-,bi- or poly-cyclic nitrogen atom-containing ring, said nitrogen atombeing the point of attachment of said heterocyclic ring with the rest ofthe molecule. Said nitrogen atom-containing ring optionally furthercontains 1 or 2 heteroatom-containing groups selected from O, C(═O), S,S(═O), S(═O)₂, NR⁸ in which R⁸ is as defined supra. Particularly,without being limited thereto, said nitrogen atom-containing ring can bea 4-membered ring, such as an azetidinyl ring, for example, or a5-membered ring, such as a pyrrolidinyl ring, for example, or a6-membered ring, such as a piperidinyl, piperazinyl, morpholinyl, orthiomorpholinyl ring, for example, or a 7-membered ring, such as adiazepanyl ring ring, for example, or an 8-, 9-, or 10-membered ring,such as a cycloheptylaminyl, cyclooctylaminyl, or cyclononylaminyl ring,respectively, for example; it being reiterated that any of theabove-mentioned nitrogen atom-containing rings can further contain 1 or2 heteroatom-containing groups selected from O, C(═O), S, S(═O), S(═O)₂,NR⁸ in which R⁸ is as defined supra. As mentioned supra, said nitrogenatom-containing ring can be bicyclic, such as, without being limitedthereto, a 5,5-membered ring, e.g. ahexahydrocyclopenta[c]pyrrol-2(1H)-yl) ring, or a 5,6-membered bicyclicring, e.g. a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring, or forexample. As mentioned supra, said nitrogen atom-containing ring can bepartially unsaturated, i.e. it can contain one or more double bonds,such as, without being limited thereto, a 2,5-dihydro-1H-pyrrolyl,4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl ring,for example, or, it may be benzo-fused, such as, without being limitedthereto, a dihydroisoquinolinyl ring, for example.

The term “3- to 10-membered heterocycloalkyl” is to be understood aspreferably meaning a saturated or partially unsaturated, monovalent,mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, 5, 6, 7, 8,or 9 carbon atoms, and one or more heteroatom-containing groups selectedfrom C(═O), O, S, S(═O), S(═O)₂, NR⁶. Particularly, said ring cancontain 2, 3, 4, or 5 carbon atoms, and one or more of theabove-mentioned heteroatom-containing groups (a “3- to 6-memberedheterocycloalkyl”), more particularly said ring can contain 4 or 5carbon atoms, and one or more of the above-mentionedheteroatom-containing groups (a “5- to 6-membered heterocycloalkyl”).Said heterocycloalkyl ring is for example, a monocyclic heterocycloalkylring such as an oxyranyl, oxetanyl, aziridinyl, azetidinyl,tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl,thiomorpholinyl, piperazinyl, trithianyl, or chinuclidinyl group.Optionally, said heterocycloalkyl ring can contain one or more doublebonds, e.g. 4H-pyranyl, 2H-pyranyl, 3H-diazirinyl,2,5-dihydro-1H-pyrrolyl, [1,3]dioxolyl, 4H-[1,3,4]thiadiazinyl,2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothiophenyl,2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl group,or, it may be benzo fused.

The term “aryl” is to be understood as preferably meaning a monovalent,aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbonring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a“C₆-C₁₄-aryl” group), particularly a ring having 6 carbon atoms (a“C₆-aryl” group), e.g. a phenyl group, or a biphenyl group, or a ringhaving 9 carbon atoms (a “C₉-aryl” group), e.g. an indanyl or indenylgroup, or a ring having 10 carbon atoms (a “C₁₋₁₀-aryl” group), e.g. atetralinyl, dihydronaphthyl, or naphthyl group, or a ring having 13carbon atoms, (a “C₁₋₃-aryl” group), e.g. a fluorenyl group, or a ringhaving 14 carbon atoms, (a “C₁₋₄-aryl” group), e.g. an anthranyl group.

The term “heteroaryl” is understood as preferably meaning a monovalent,aromatic, mono- or bicyclic aromatic ring system having 5, 6, 7, 8, 9,10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl”group), particularly 5 or 6 or 9 or 10 atoms, and which contains atleast one heteroatom which may be identical or different, saidheteroatom being such as oxygen, nitrogen or sulfur, and can bemonocyclic, bicyclic, or tricyclic, and in addition in each case can bebenzocondensed. Particularly, heteroaryl is selected from thienyl,furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,thia-4H-pyrazolyl etc., and benzo derivatives thereof, such as, forexample, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl,benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; orpyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzoderivatives thereof, such as, for example, quinolinyl, quinazolinyl,isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzoderivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc.More particularly, heteroaryl is selected from pyridyl, benzofuranyl,benzisoxazolyl, indazolyl, quinazolinyl, thienyl, quinolinyl,benzothienyl, pyrazolyl, or furanyl.

More particularly, said heteroaryl group may be selected from thefollowing:

in which * indicates the point of attachment of said heteroaryl groupwith the rest of the molecule.

In general, and unless otherwise mentioned, the heteroarylic orheteroarylenic radicals include all the possible isomeric forms thereof,e.g. the positional isomers thereof. Thus, for some illustrativenon-restricting example, the term pyridinyl or pyridinylene includespyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene,pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienyleneincludes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.

The term “C₁-C₆”, as used throughout this text, e.g. in the context ofthe definition of “C₁-C₆-alkyl”, “C₁-C₆-haloalkyl”, “C₁-C₆-alkoxy”, or“C₁-C₆-haloalkoxy” is to be understood as meaning an alkyl group havinga finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6carbon atoms. It is to be understood further that said term “C₁-C₆” isto be interpreted as any sub-range comprised therein, e.g. C₁-C₆, C₂-C₅,C₃-C₄, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, C₁-C₆; particularly C₁-C₂, C₁-C₃,C₁-C₄, C₁-C₅, C₁-C₆; more particularly C₁-C₄; in the case of“C₁-C₆-haloalkyl” or “C₁-C₆-haloalkoxy” even more particularly C₁-C₂.

Similarly, as used herein, the term “C₂-C₆”, as used throughout thistext, e.g. in the context of the definitions of “C₂-C₆-alkenyl” and“C₂-C₆-alkynyl”, is to be understood as meaning an alkenyl group or analkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2,3, 4, 5, or 6 carbon atoms. It is to be understood further that saidterm “C₂-C₆” is to be interpreted as any sub-range comprised therein,e.g. C₂-C₆, C₃-C₅, C₃-C₄, C₂-C₃, C₂-C₄, C₂-C₅; particularly C₂-C₃.

Further, as used herein, the term “C₃-C₆”, as used throughout this text,e.g. in the context of the definition of “C₃-C₆-cycloalkyl”, is to beunderstood as meaning a cycloalkyl group having a finite number ofcarbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to beunderstood further that said term “C₃-C₆” is to be interpreted as anysub-range comprised therein, e.g. C₃-C₆, C₄-C₅, C₃-C₅, C₃-C₄, C₄-C₆,C₅-C₆; particularly C₃-C₆.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Ring system substituent means a substituent attached to an aromatic ornonaromatic ring system which, for example, replaces an availablehydrogen on the ring system.

As used herein, the term “one or more times”, e.g. in the definition ofthe substituents of the compounds of the general formulae of the presentinvention, is understood as meaning “one, two, three, four or fivetimes, particularly one, two, three or four times, more particularlyone, two or three times, even more particularly one or two times”.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of this invention may contain one or more asymmetriccentre, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration, resulting in racemic mixtures in the case of asingle asymmetric centre, and diastereomeric mixtures in the case ofmultiple asymmetric centres. In certain instances, asymmetry may also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds.

Substituents on a ring may also be present in either cis or trans form.It is intended that all such configurations (including enantiomers anddiastereomers), are included within the scope of the present invention.

Preferred compounds are those which produce the more desirablebiological activity. Separated, pure or partially purified isomers andstereoisomers or racemic or diastereomeric mixtures of the compounds ofthis invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivatisation, optimally chosen to maximise the separationof the enantiomers. Suitable chiral HPLC columns are manufactured byDiacel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivatisation, are also useful. The optically active compounds of thisinvention can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

In order to limit different types of isomers from each other referenceis made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of thecompounds of the present invention as single stereoisomers, or as anymixture of said stereoisomers, in any ratio. Isolation of a singlestereoisomer, e.g. a single enantiomer or a single diastereomer, of acompound of the present invention may be achieved by any suitable stateof the art method, such as chromatography, especially chiralchromatography, for example.

Further, the compounds of the present invention may exist as tautomers.For example, any compound of the present invention which contains apyrazole moiety as a heteroaryl group for example can exist as a 1Htautomer, or a 2H tautomer, or even a mixture in any amount of the twotautomers, or a triazole moiety for example can exist as a 1H tautomer,a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said1H, 2H and 4H tautomers, viz.:

The present invention includes all possible tautomers of the compoundsof the present invention as single tautomers, or as any mixture of saidtautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, andco-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example asstructural element of the crystal lattice of the compounds. The amountof polar solvents, in particular water, may exist in a stoichiometric ornon-stoichiometric ratio. In the case of stoichiometric solvates, e.g. ahydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc.solvates or hydrates, respectively, are possible. The present inventionincludes all such hydrates or solvates.

Further, the compounds of the present invention can exist in free form,e.g. as a free base, or as a free acid, or as a zwitterion, or can existin the form of a salt. Said salt may be any salt, either an organic orinorganic addition salt, particularly any pharmaceutically acceptableorganic or inorganic addition salt, customarily used in pharmacy.

The term “pharmaceutically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention. For example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of thepresent invention may be, for example, an acid-addition salt of acompound of the present invention bearing a nitrogen atom, in a chain orin a ring, for example, which is sufficiently basic, such as anacid-addition salt with an inorganic acid, such as hydrochloric,hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitricacid, for example, or with an organic acid, such as formic, acetic,acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic,heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic,2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic,dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic,methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic,mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic,sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium or magnesium salt, an ammonium salt ora salt with an organic base which affords a physiologically acceptablecation, for example a salt with N-methyl-glucamine, dimethyl-glucamine,ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine,ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base,1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groupsmay be quaternised with such agents as lower alkyl halides such asmethyl, ethyl, propyl, and butyl chlorides, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

Those skilled in the art will further recognise that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

As used herein, the term “in vivo hydrolysable ester” is understood asmeaning an in vivo hydrolysable ester of a compound of the presentinvention containing a carboxy or hydroxy group, for example, apharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include for examplealkyl, cycloalkyl and optionally substituted phenylalkyl, in particularbenzyl esters, C₁-C₆ alkoxymethyl esters, e.g. methoxymethyl, C₁-C₆alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters,C₃-C₈ cycloalkoxy-carbonyloxy-C₁-C₆ alkyl esters, e.g.1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g.5-methyl-1,3-dioxolen-2-onylmethyl; and C₁-C₆-alkoxycarbonyloxyethylesters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxygroup in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the present inventioncontaining a hydroxy group includes inorganic esters such as phosphateesters and [alpha]-acyloxyalkyl ethers and related compounds which as aresult of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of invivo hydrolysable ester forming groups for hydroxy include alkanoyl,benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. The present invention covers allsuch esters.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorphs, or as a mixture of more than one polymorphs, inany ratio.

In accordance with a second aspect, the present invention coverscompounds of general formula (I), supra, in which:

-   X represents an —SR⁵, —S(═O)R⁵, —S(═O)₂R⁵, —S(═O)(═NR^(5a))R^(5b),    or —S(═O)₂N(R^(5b))R^(5c) group;-   R¹ represents a hydrogen atom or a halogen atom, or a —CN,    C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-,    HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN, —C(═O)N(H)R⁸,    —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶, or —N(R^(8a))R^(8b) group;-   R² represents a —C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b), —N(H)C(═O)R⁸,    —N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b),    —N(H)C(═O)N(R^(8a))R^(8b), —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)S(═O)R⁸,    —N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b) group; or    a group selected from:

-   -   (in which * indicates the point of attachment of said group with        the rest of the molecule);

-   R^(3a), R^(3b)    -   represent, independently from one another, a hydrogen atom or a        halogen atom, or a —CN, C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,        —(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl,        —(CH₂)_(m)-(3- to 7-membered heterocycloalkyl),        aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,        R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,        C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-,        C₃-C₆-cycloalkyl-, a 3- to 7-membered heterocycloalkyl,        C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-,        C₁-C₆-alkyl-aryl-, heteroaryl, —C(═O)R⁸, —C(═O)N(H)R⁸,        —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶, —N(R^(8a))R^(8b), —NO₂,        —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂,        —N(H)C(═O)N(H)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),        —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸,        —N(R^(8a))C(═O)OR^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),        —N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b),        —OH, —OR⁸, —O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸,        —S(═O)R⁸, —S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸,        —S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b), or —S(═O)(═NR^(8a))R^(8b)        group;    -   said C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,        —(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl,        aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a        3- to 7-membered heterocycloalkyl, C₂-C₆-alkenyl-,        C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-, C₁-C₆-alkyl-aryl-,        heteroaryl,    -   being optionally substituted, identically or differently, with        1, 2, 3, or 4 R⁷ groups;

-   R^(4a), e, R^(4c), R^(4d)    -   represent, independently from each other, a hydrogen or halogen        atom, or a —CN, halo-C₁-C₆-alkyl-, R^(8a)(R^(8b))N—C₁-C₆-alkyl-,        HO—C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl-,        halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, —C(═O)R⁸, —C(═O)N(H)R⁸,        —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁸, —N(R^(8a))R^(8b), —NO₂,        —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),        —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸,        —N(R^(8a))C(═O)OR^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),        —N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b),        —OH, —OR⁸, —O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸,        —S(═O)R⁸, —S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸,        —S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b), —S(═O)(═NR^(8a))R^(8b)        group;

-   or

-   R^(4c), together with R², forms an *N(R⁶)—N═C*—NH₂ group, (in    which * indicates the point of attachment of said group with the    rest of the molecule);

-   R⁵, R^(5b), R^(5c),    -   represent, independently from each other, a hydrogen atom, or a        C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,        —(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl,        —(CH₂)_(m)-(3- to 7-membered heterocycloalkyl),        aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,        R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,        C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-,        C₃-C₆-cycloalkyl-, a 3- to 7-membered heterocycloalkyl,        C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-,        heteroaryl group;    -   said C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,        —(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl,        —(CH₂)_(m)-(3- to 7-membered heterocycloalkyl),        aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,        R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,        C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-,        C₃-C₆-cycloalkyl-, a 3- to 7-membered heterocycloalkyl,        C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-,        heteroaryl,    -   being optionally substituted, identically or differently, with        1, 2, 3, or 4 R⁷ groups,;

-   R^(5a) represents a hydrogen atom or a —C(═O)—C₁-C₆-alkyl, or    —C(═O)—C₃-C₆-cycloalkyl group;    -   said C₁-C₆-alkyl being optionally substituted, identically or        differently, with one or more halogen atom;

-   R⁶, R^(6a)    -   represent, independently from each other, a hydrogen atom or a        C₁-C₆-alkyl or C₃-C₆-cycloalkyl group,

-   R⁷ represents a hydrogen or halogen atom, or a —CN,    halo-C₁-C₆-alkyl-, C₂-C₆-alkenyl, —C(═O)R⁸, —C(═O)N(H)R⁸,    —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁸, —N(R^(8a))R^(8b), —NO₂,    —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b), —N(R⁸)C(═O)OR^(8a),    —N(H)C(═O)N(R^(8a))R^(8b), —N(R⁸)C(═O)N(R^(8a))R^(8b), —OR⁸,    —O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,    —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸,    —S(═O)₂N(R^(8a))R^(8b) group;

-   R⁸, R^(8a), R^(8b),    -   represent, independently from each other, a hydrogen atom, or a        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, 3- to 7-membered        heterocycloalkyl, aryl, heteroaryl, aryl-C₁-C₆-alkyl-, or        heteroaryl-C₁-C₆-alkyl- group;

-   m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

-   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In accordance with a third aspect, the present invention coverscompounds of general formula (I), supra, in which:

-   X represents an —SR⁵, —S(═O)R⁵, —S(═O)₂R⁵, —S(═O)(═NR^(5a))R^(5b),    or —S(═O)₂N(R^(5b))R^(5c) group;-   R¹ represents a hydrogen atom or a halogen atom, or a —CN,    C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-,    HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN, —C(═O)N(H)R⁸,    —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶ or —N(R^(8a))R^(8b) group;-   R² represents a —C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b), —N(H)C(═O)R⁸,    —N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b),    —N(H)C(═O)N(R^(8a))R^(8b), —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)S(═O)R⁸,    —N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b) group; or    a group selected from:

-   -   (in which * indicates the point of attachment of said group with        the rest of the molecule);

-   R^(3a), R^(3b)    -   represent, independently from one another, a hydrogen atom or a        halogen atom, or a —CN, C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,        —(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl,        —(CH₂)_(m)-(3- to 7-membered heterocycloalkyl),        aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,        R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,        C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-,        C₃-C₆-cycloalkyl-, a 3- to 7-membered heterocycloalkyl,        C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-,        C₁-C₆-alkyl-aryl-, heteroaryl, —C(═O)R⁸, —C(═O)N(H)R⁸,        —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶, —N(R^(8a))R^(8b), —NO₂,        —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂,        —N(H)C(═O)N(H)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),        —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸,        —N(R^(8a))C(═O)OR^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),        —N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b),        —OH, —OR⁸, —O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸,        —S(═O)R⁸, —S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸,        —S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b), or —S(═O)(═NR^(8a))R^(8b)        group;    -   said C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,        —(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl,        aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a        3- to 7-membered heterocycloalkyl, C₂-C₆-alkenyl-,        C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-, C₁-C₆-alkyl-aryl-,        heteroaryl, being optionally substituted, identically or        differently, with 1, 2, 3, or 4 R⁷ groups;

-   R^(4a), R^(4b), R^(4c), R^(4d)    -   represent a hydrogen atom

-   or

-   R^(4c), together with R², forms an *N(R⁶)—N═C*—NH₂ group, (in    which * indicates the point of attachment of said group with the    rest of the molecule);

-   R⁵, R^(5b), R^(5c),    -   represent, independently from each other, a hydrogen atom, or a        C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,        —(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl,        —(CH₂)_(m)-(3- to 7-membered heterocycloalkyl),        aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,        R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,        C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-,        C₃-C₆-cycloalkyl-, a 3- to 7-membered heterocycloalkyl,        C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-,        heteroaryl group;    -   said C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,        —(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl,        —(CH₂)_(m)-(3- to 7-membered heterocycloalkyl),        aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,        R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,        C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-,        C₃-C₆-cycloalkyl-, a 3- to 7-membered heterocycloalkyl,        C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-,        heteroaryl,    -   being optionally substituted, identically or differently, with        1, 2, 3, or 4 R⁷ groups,;

-   R^(5a) represents a hydrogen atom or a —C(═O)—C₁-C₆-alkyl, or    —C(═O)—C₃-C₆-cycloalkyl group;    -   said C₁-C₆-alkyl being optionally substituted, identically or        differently, with one or more halogen atom;

-   R⁶, R^(6a)    -   represent, independently from each other, a hydrogen atom or a        C₁-C₆-alkyl or C₃-C₆-cycloalkyl group;

-   R⁷ represents a hydrogen or halogen atom, or a —CN,    halo-C₁-C₆-alkyl-, C₂-C₆-alkenyl, —C(═O)R⁸, —C(═O)N(H)R⁸,    —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁸, —N(R^(8a))R^(8b), —NO₂,    —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),    —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(R⁸)C(═O)OR^(8a), —OR⁸, —O(C═O)R⁸,    —O(C═O)N(R^(8a))R^(8b), —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,    —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸,    —S(═O)₂N(R^(8a))R^(8b) group;

-   R⁸, R^(8a), R^(8b),    -   represent, independently from each other, a hydrogen atom, or a        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, 3- to 7-membered        heterocycloalkyl, aryl, heteroaryl, aryl-C₁-C₆-alkyl-, or        heteroaryl-C₁-C₆-alkyl- group;

-   m is an integer of 1, 2 or 3;    or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In accordance with a fourth aspect, the present invention coverscompounds of general formula (I), supra, in which:

-   X represents an —SR⁵, —S(═O)R⁵, —S(═O)₂R⁵, —S(═O)(═NR^(5a))R^(5b),    or —S(═O)₂N(R^(5b))R^(5c) group;-   R¹ represents a hydrogen atom;-   R² represents a —C(═O)N(H)R⁸ group;    -   or an

group,

-   -   (in which * indicates the point of attachment of said group with        the rest of the molecule);

-   R^(3a) represents a hydrogen atom;

-   R^(3b) represents a hydrogen atom or a halogen atom, or a    C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, aryl-, C₁-C₆-alkyl-aryl-, or    heteroaryl group;    -   said C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, aryl-, C₁-C₆-alkyl-aryl- or        heteroaryl, being optionally substituted, identically or        differently, with 1, 2, 3, or 4 R⁷ groups;

-   R^(4a), R^(4b), R^(4c), R^(4d)    -   represent a hydrogen atom,

-   or

-   R^(4c), together with R², forms an *N(R⁶)—N═C*—NH₂ group, (in    which * indicates the point of attachment of said group with the    rest of the molecule);

-   R⁵, R^(5b), R^(5c),    -   represent, independently from each other, a C₁-C₆-alkyl-,        —(CH₂)_(m)-(3- to 7-membered heterocycloalkyl),        heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl- group;    -   said C₁-C₆-alkyl-, —(CH₂)_(m)-(3- to 7-membered        heterocycloalkyl), heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,    -   being optionally substituted, identically or differently, with        1, 2, 3, or 4 R⁷ groups;

-   R^(5a) represents a hydrogen atom or a —C(═O)—C₁-C₆-alkyl, or    —C(═O)—C₃-C₆-cycloalkyl group;    -   said C₁-C₆-alkyl being optionally substituted, identically or        differently, with one or more halogen atom;

-   R⁶, R^(6a)    -   represent, independently from each other, a hydrogen atom or a        C₁-C₆-alkyl or C₃-C₆-cycloalkyl group;

-   R⁷ represents a hydrogen or halogen atom, or a halo-C₁-C₆-alkyl-,    C₂-C₆-alkenyl, —C(═O)N(H)R⁸, —N(R^(8a))R^(8b), —N(H)C(═O)R⁸,    —N(R^(8a))C(═O)R^(8b), —N(R⁸)C(═O)OR^(8a), —OR⁸, —O(C═O)R⁸,    —O(C═O)N(R^(8a))R^(8b) group;

-   R⁸, R^(8a), R^(8b),    -   represent, independently from each other, a hydrogen atom, or a        C₁-C₆-alkyl or C₃-C₆-cycloalkyl group;

-   m is an integer of 1;    or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In an embodiment of the above-mentioned aspects, the invention relatesto compounds of formula (I), wherein:

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein X represents an —SR⁵,—S(═O)R⁵, —S(═O)₂R⁵, —S(═O)(═NR^(5a))R^(5b), or —S(═O)₂N(R^(5b))R^(5c)group.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R¹ represents a hydrogenatom or a halogen atom, or a —CN, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-,C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, —C(═O)R⁸, —C(═O)N(H)R⁸,—C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶, —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸,—N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b),—N(H)C(═O)N(R^(8a))R^(8b), —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸,—N(R^(8a))C(═O)OR^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),—N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸,—O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸,—S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸,—S(═O)₂N(R^(8a))R^(8b), or —S(═O)(═NR^(8a))R^(8b) group.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R² represents a hydrogenatom or a halogen atom, or a —CN, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-,C₂-C₆-alkenyl-, or C₂-C₆-alkynyl-, —C(═O)R⁸, —C(═O)N(H)R⁸,—C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶, —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸,—N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b),—N(H)C(═O)N(R^(8a))R^(8b), —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸,—N(R^(8a))C(═O)OR^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),—N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸,—O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸,—S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸,—S(═O)₂N(R^(8a))R^(8b), or —S(═O)(═NR^(8a))R^(8b) group;

or a group selected from:

(in which * indicates the point of attachment of said group with therest of the molecule).

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R^(3a), R^(3b) represent,independently from one another, a hydrogen atom or a halogen atom, or a—CN, C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to 7-memberedheterocycloalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-,—C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, C₁-C₆-alkyl-aryl-, heteroaryl, —C(═O)R⁸, —C(═O)N(H)R⁸,—C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶, —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸,—N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b),—N(H)C(═O)N(R^(8a))R^(8b), —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸,—N(R^(8a))C(═O)OR^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),—N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸,—O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸,—S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸,—S(═O)₂N(R^(8a))R^(8b), or —S(═O)(═NR^(8a))R^(8b) group;

said C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,C₃-C₆-cycloalkyl-, a 3- to 7-membered heterocycloalkyl, C₂-C₆-alkenyl-,C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-, C₁-C₆-alkyl-aryl-,heteroaryl, being optionally substituted, identically or differently,with 1, 2, 3, or 4 R⁷ groups.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R^(4a), R^(4b), R^(4c),R^(4d) represent, independently from each other, a hydrogen or halogenatom, or a —CN, halo-C₁-C₆-alkyl-, R^(8a)(R^(8b))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, —C(═O)R⁸, —C(═O)N(H)R⁸,—C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁸, —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸,—N(R^(8a))C(═O)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),—N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸, —N(R^(8a))C(═O)OR^(8b),—N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸,—NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸, —O(C═O)R⁸,—O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,—S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b),or —S(═O)(═NR^(8a))R^(8b) group;

-   or-   R^(4c), together with R², forms an *N(R⁶)—N═C*—NH₂ group, (in    which * indicates the point of attachment of said group with the    rest of the molecule).

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R⁵, R^(5b), R^(5c),represent, independently from each other, a hydrogen atom, or aC₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to 7-memberedheterocycloalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-,—C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, heteroaryl group;

said C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to 7-memberedheterocycloalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-,—C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, heteroaryl,being optionally substituted, identically or differently, with 1, 2, 3,or 4 R⁷ groups.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R^(5a) represents ahydrogen atom or a —C(═O)—C₁-C₆-alkyl, or —C(═O)—C₃-C₆-cycloalkyl group;

said C₁-C₆-alkyl being optionally substituted, identically ordifferently, with one or more halogen atom.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R⁶, R^(6a) represent,independently from each other, a hydrogen atom or a C₁-C₆-alkyl orC₃-C₆-cycloalkyl group.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R⁷ represents a hydrogen orhalogen atom, or a —CN, halo-C₁-C₆-alkyl-, R^(8a)(R^(8b))N—C₁-C₆-alkyl-,HO—C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₂-C₆-alkenyl, —C(═O)R⁸, —C(═O)N(H)R⁸,—C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁸, —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸,—N(R^(8a))C(═O)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),—N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸, —N(R^(8a))C(═O)OR^(8b),—N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸,—NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸, —O(C═O)R⁸,—O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,—S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b),or —S(═O)(═NR^(8a))R^(8b) group.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R⁸, R^(8a), R^(8b),represent, independently from each other, a hydrogen atom, or aC₁-C₆-alkyl, C₃-C₆-cycloalkyl, 3- to 7-membered heterocycloalkyl, aryl,heteroaryl, aryl-C₁-C₆-alkyl-, or heteroaryl-C₁-C₆-alkyl- group.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein m is an integer of 1, 2, 3,4, 5, 6, 7, 8, 9 or 10.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R¹ represents a hydrogenatom or a halogen atom, or a —CN, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,—C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶, or —N(R^(8a))R^(8b)group.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R² represents a—C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b), —N(H)C(═O)R⁸,—N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b),—N(H)C(═O)N(R^(8a))R^(8b), —N(H)S(═O)N(R^(8a))R^(8b), —N(H)S(═O)R⁸,—N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸, or —NR^(8a)S(═O)₂R^(8b) group or agroup selected from:

(in which * indicates the point of attachment of said group with therest of the molecule).

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R^(3a), R^(3b) represent,independently from one another, a hydrogen atom or a halogen atom, or a—CN, C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to 7-memberedheterocycloalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-,—C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, C₁-C₆-alkyl-aryl-, heteroaryl, —C(═O)R⁸, —C(═O)N(H)R⁸,—C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶, —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸,—N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b),—N(H)C(═O)N(R^(8a))R^(8b), —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸,—N(R^(8a))C(═O)OR^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),—N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸,—O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸,—S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸,—S(═O)₂N(R^(8a))R^(8b), or —S(═O)(═NR^(8a))R^(8b) group;

said C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,C₃-C₆-cycloalkyl-, a 3- to 7-membered heterocycloalkyl, C₂-C₆-alkenyl-,C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-, C₁-C₆-alkyl-aryl-,heteroaryl, being optionally substituted, identically or differently,with 1, 2, 3, or 4 R⁷ groups.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R^(4a), R^(4b), R^(4c),R^(4d) represent, independently from each other, a hydrogen or halogenatom, or a —CN, halo-C₁-C₆-alkyl-, R^(8a)(R^(8b))N—C₁-C₆-alkyl-,HO—C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, —C(═O)R⁸, —C(═O)N(H)R⁸,—C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁸, —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸,—N(R^(8a))C(═O)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),—N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸, —N(R^(8a))C(═O)OR^(8b),—N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸,—NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸, —O(C═O)R⁸,—O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,—S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b),or —S(═O)(═NR^(8a))R^(8b) group;

-   or-   R^(4c), together with R², forms an *N(R⁶)—N═C*—NH₂ group, (in    which * indicates the point of attachment of said group with the    rest of the molecule).

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R⁵, R^(5b), R^(5c),represent, independently from each other, a hydrogen atom, or aC₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to 7-memberedheterocycloalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-,—C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, heteroaryl;

said C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to 7-memberedheterocycloalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-,—C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, heteroaryl,being optionally substituted, identically or differently, with 1, 2, 3,or 4 R⁷ groups.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R^(ya) represents ahydrogen atom or a —C(═O)—C₁-C₆-alkyl, or —C(═O)—C₃-C₆-cycloalkyl group;

said C₁-C₆-alkyl being optionally substituted, identically ordifferently, with one or more halogen atom.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R⁶, R^(6a) represent,independently from each other, a hydrogen atom or a C₁-C₆-alkyl orC₃-C₆-cycloalkyl group.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R⁷ represents a hydrogen orhalogen atom, or a —CN, halo-C₁-C₆-alkyl-, C₂-C₆-alkenyl, —C(═O)R⁸,—C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁸, —N(R^(8a))R^(8b), —NO₂,—N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b), —N(R⁸)C(═O)OR^(8a),—N(H)C(═O)N(R^(8a))R^(8b), —N(R⁸)C(═O)N(R^(8a))R^(8b), —OR⁸, —O(C═O)R⁸,—O(C═O)N(R^(8a))R^(8b), —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,—S(═O)N(R^(8a))R^(8b), —S(—O₂)R⁸, —S(═O)₂N(H)R⁸, or—S(═O)₂N(R^(8a))R^(8b) group.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R⁸, R^(8a), R^(8b), R^(8b)represent, independently from each other, a hydrogen atom, or aC₁-C₆-alkyl, C₃-C₆-cycloalkyl, 3- to 7-membered heterocycloalkyl, aryl,heteroaryl, aryl-C₁-C₆-alkyl-, or heteroaryl-C₁-C₆-alkyl- group.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R^(4a), R^(4b), R^(4c),R^(4d) represent a hydrogen atom,

orR^(4c), together with R², forms an *N(R⁶)—N═C*—NH₂ group, (in which *indicates the point of attachment of said group with the rest of themolecule).

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R¹ represents a hydrogenatom.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R² represents a

—C(═O)N(H)R⁸ group;or an

group,

-   -   (in which * indicates the point of attachment of said group with        the rest of the molecule).

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R^(3a) represents ahydrogen atom.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R^(3b) represents ahydrogen atom or a halogen atom, or a C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,aryl-, C₁-C₆-alkyl-aryl-, or heteroaryl group;

said C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, aryl-, C₁-C₆-alkyl-aryl- orheteroaryl group being optionally substituted, identically ordifferently, with 1, 2, 3, or 4 R⁷ groups.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R^(4a), R^(4b), R^(4c),R^(4d) represent a hydrogen atom,

orR^(4c), together with R², forms an *N(R⁶)—N═C*—NH₂ group, (in which *indicates the point of attachment of said group with the rest of themolecule).

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R⁵, R^(5b), R^(5c),represent, independently from each other, a C₁-C₆-alkyl-, —(CH₂)_(m)-(3-to 7-membered heterocycloalkyl), heteroaryl-C₁-C₆-alkyl-,halo-C₁-C₆-alkyl- group;

said C₁-C₆-alkyl-, —(CH₂)_(m)-(3- to 7-membered heterocycloalkyl),heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,being optionally substituted, identically or differently, with 1, 2, 3,or 4 R⁷ groups.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R^(5a) represents ahydrogen atom or a —C(═O)—C₁-C₆-alkyl, or —C(═O)—C₃-C₆-cycloalkyl group;

said C₁-C₆-alkyl being optionally substituted, identically ordifferently, with one or more halogen atom.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R⁶, R^(6a) represent,independently from each other, a hydrogen atom or a C₁-C₆-alkyl orC₃-C₆-cycloalkyl group.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R⁷ represents a hydrogen orhalogen atom, or a halo-C₁-C₆-alkyl-, C₂-C₆-alkenyl, —C(═O)N(H)R⁸,—N(R^(8a))R^(8b), —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b),—N(R⁸)C(═O)OR^(8a), —OR⁸, —O(C═O)R⁸, or —O(C═O)N(R^(8a))R^(8b) group.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein R⁸, R^(8a), R^(8b),represent, independently from each other, a hydrogen atom, or aC₁-C₆-alkyl or C₃-C₆-cycloalkyl group.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein m is an integer of 1, 2 or3.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein m is an integer of 1.

It is to be understood that the present invention relates to anysub-combination within any embodiment of the present invention ofcompounds of general formula (I), supra.

More particularly still, the present invention covers compounds ofgeneral formula (I) which are disclosed in the Example section of thistext, infra.

In accordance with another aspect, the present invention covers methodsof preparing compounds of the present invention, said methods comprisingthe steps as described in the Experimental Section herein.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (I), particularly in themethod described herein. In particular, the present invention covers:

a) compounds of general formula (VIII):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d) are asdefined for the compound of general formula (I) of the present inventionas defined in the claims, or a stereoisomer, a tautomer, an N-oxide, ahydrate, a solvate, or a salt thereof, or a mixture of same;andb) compounds of general formula (VII):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d) are asdefined for the compound of general formula (I) of the present inventionas defined in the claims.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula (VIII):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d) are asdefined for the compound of general formula (I) of the present inventionas defined in the claims, for the preparation of a compound of generalformula (Ia):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d), R^(5b)and R^(5c) are as defined for the compound of general formula (I) of thepresent invention as defined in the claims.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula (VII):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d) are asdefined for the compound of general formula (I) of the present inventionas defined in the claims, for the preparation of compounds of generalformula (Ib):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d), and R⁵are as defined for the compound of general formula (I) of the presentinvention as defined in the claims.

EXPERIMENTAL SECTION

The following Table lists the abbreviations used in this paragraph, andin the Examples section. NMR peak forms are stated as they appear in thespectra, possible higher order effects have not been considered.

Abbreviation Meaning Boc tert-butyloxycarbonyl c- Cyclo- DCMDichloromethane DMSO Dimethyl sulfoxide NMR nuclear magnetic resonancespectroscopy: chemical shifts (δ) are given in ppm. Rt Room temperaturer.t. Room temperature

The schemes and procedures described below illustrate general syntheticroutes to the compounds of general formula (I) of the invention and arenot intended to be limiting. It is clear to the person skilled in theart that the order of transformations as exemplified in the Schemes canbe modified in various ways. The order of transformations exemplified inthe Schemes is therefore not intended to be limiting. In addition,interconversion of any of the substituents, R¹, R², R³, R⁴, R⁵, R⁶, R⁷or R⁸ can be achieved before and/or after the exemplifiedtransformations. These modifications can be such as the introduction ofprotecting groups, cleavage of protecting groups, reduction or oxidationof functional groups, halogenation, metallation, substitution or otherreactions known to the person skilled in the art. These transformationsinclude those which introduce a functionality which allows for furtherinterconversion of substituents. Appropriate protecting groups and theirintroduction and cleavage are well-known to the person skilled in theart (see for example T. W. Greene and P. G. M. Wuts in Protective Groupsin Organic Synthesis, 3^(rd) edition, Wiley 1999). Specific examples aredescribed in the subsequent paragraphs.

A first reaction scheme is outlined infra:

Synthesis of Compounds of General Formula (I) of the Present InventionScheme 1

Compounds of general formula I can be synthesized according to theprocedure depicted in Scheme 1.

Intermediates of II and V may be commercially available or can besynthesized according to procedures known to persons skilled in the art.Y represents a leaving group, which is understandable to the personskilled in the art and which may include, for example, a halogen atom.Said leaving group in position 8 of the compound of formula (II) can besubstituted by methanethiolate in an inert solvent like an alcohol togive methylsulfanyl compounds of general formula III or VI,respectively. Halogenation at the five membered ring to yield compoundsof general formula IV is achieved by using halogenation reagents likeN-iodosuccinimide, or N-bromosuccinimide or N-chlorosuccinimide, forexample, in an inert solvent like N,N-dimethylformamide or1-methylpyrrolidin-2-one, for example, at temperatures ranging from roomtemperature to the boiling point of the solvent, for example.

Compounds of general formula VI can also be obtained from compounds ofgeneral formula IV via a coupling reaction for example, usingarylboronic acids or arylboronic esters for example, using a suitablecatalyst, such as a palladium catalyst for example, optionally in thepresence of a suitable base like potassium carbonate for example, in aninert solvent like tetrahydrofuran for example.

Examples of such coupling reactions may be found in the textbookentitled “Metal-Catalyzed Cross-Coupling Reactions”, Armin de Meijere(Editor), Francois Diederich (Editor) September 2004, Wiley InterscienceISBN: 978-3-527-30518-6.

Compounds of general formula Ia can be obtained in a two step sequencestarting from compounds of general formula V which are subjected to ahalogen metal exchange reaction followed by subsequent reaction withSO₂Cl₂ to give intermediate compounds of general formula VIII that canbe converted by reaction with suitable amines to sulfonamides of generalformula Ia.

Compounds of general formula Ib can be obtained in a two step sequencestarting from compounds of general formula VI which are oxidized to themethylsulfones of general formula VII using oxidation reagents like3-chlorobenzenecarboperoxoic acid or dimethyldioxirane in inert solventslike dichloromethane or acetone, respectively. The methylsulfone can besubstituted by thiolates in an inert solvent like an alcohol to givecompounds of general formula Ib.

Compounds of general formula Id can be obtained by oxidation ofcompounds of general formula Ib as described for compounds of generalformula VII.

Compounds of general formula Ie can be obtained by oxidation ofcompounds of general formula Ib or Id as described for compounds ofgeneral formula VII.

Depending on the stoichiometric ratio of oxidation reagent to compoundsof general formula Ib mixtures of compounds of general formulae Id andle can be obtained in one reaction.

Compounds of general formula Ic can be obtained from compounds ofgeneral formula Ib by reaction with acetamides in the presence of lewisacids like magnesium oxide, for example, an oxidizing agent likediacetoxy(phenyl)-13-iodane for example, and a suitable catalyst likerhodium(II)diacetate for example, in an inert solvent likedichloromethane, for example.

In an embodiment, the present invention relates to a method of preparingcompounds of general formula (Ia):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d), R^(5b)and R^(5c) are as defined for the compound of general formula (I) of thepresent invention as defined in the claims,in which method an intermediate compound of general formula (VIII):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d) are asdefined for the compound of general formula (I) of the present inventionas defined in the claims, is allowed to react with an amine of generalformula (VIIIa):

in which R^(5b) and R^(5c) are as defined for the compound of generalformula (I) of the present invention as defined in the claims,thus providing a compound of general formula (Ia).

In another embodiment, the present invention relates to a method ofpreparing compounds of general formula (Ib):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d), and R⁵are as defined for the compound of general formula (I) of the presentinvention as defined in the claims,in which method an intermediate methyl sulphone compound of generalformula (VII):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d) are asdefined for the compound of general formula (I) of the present inventionas defined in the claims,is allowed to react with a thiol of general formula (VIIa), which isdeprotonated:

in which R⁵ is as defined for the compound of general formula (I) of thepresent invention as defined in the claims.

The compounds and intermediates produced according to the methods of theinvention may require purification. Purification of organic compounds iswell known to the person skilled in the art and there may be severalways of purifying the same compound. In some cases, no purification maybe necessary. In some cases, the compounds may be purified bycrystallisation. In some cases, impurities may be stirred out using asuitable solvent. In some cases, the compounds may be purified bychromatography, particularly flash chromatography, using for examplepre-packed silica gel cartridges, e.g. from Separtis such as Isolute®Flash silica gel (silica gel chromatography) or Isolute® Flash NH2silica gel (aminophase-silica-gel chromatography) in combination with asuitable chromatographic system such as a Flashmaste(Separtis) or anIsolera system (Biotage) and eluents such as, for example, gradients ofhexane/ethyl acetate or DCM/methanol. In some cases, the compounds maybe purified by preparative HPLC using, for example, a Watersautopurifier equipped with a diode array detector and/or on-lineelectrospray ionisation mass spectrometer in combination with a suitablepre-packed reverse phase column and eluants such as, for example,gradients of water and acetonitrile which may contain additives such astrifluoroacetic acid, formic acid or aqueous ammonia.

Names of compounds were generated using ACD/Name Batch ver. 12.00 orACD/Name Batch ver. 12.01. Names of compounds in table format weregenerated using ACD/Name Batch ver. 12.00.

The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure.

General: All reactions were run under an atmosphere of argon in degassedsolvents unless stated otherwise.

SYNTHESIS OF INTERMEDIATE EXAMPLES Intermediate Example 16-Bromo-8-(methylsulfanyl)imidazo[1,2-a]pyrazine

A mixture of 61.0 g (220 mmol) 6,8-dibromoimidazo[1,2-a]pyrazine (CAS63744-22-9), 610 mL methanol and 30.2 g sodium methanethiolate wasstirred at 23° C. for 16 hours, poured into 6 L water and cooled until aprecipitate had formed. The product was filtered off and dried at 60° C.to give 38.5 g (72%) of the title compound which was used withoutfurther purification.

Intermediate Example 26-Bromo-3-iodo-8-(methylsulfanyl)imidazo[1,2-a]pyrazine

To a solution of 5.23 g (21.4 mmol)6-Bromo-8-(methylsulfanyl)imidazo[1,2-a]pyrazine which was preparedaccording to Intermediate Example 1, supra, in 142 mLN,N-dimethylformamide were added 5.06 g N-iodosuccinimide and themixture was stirred at 60° C. for 6.5 hours. Most of the solvent wasremoved under reduced pressure, water was added and the residueextracted with dichloromethane. The organic phase was washed with water,aqueous sodium thiosulfate and dried over sodium sulfate. Afterfiltration and removal of the solvent 7.61 g (96%) of the title compoundwere isolated that were used without further purification.

Example 14-[6-Bromo-8-(methylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamide

A mixture of 7.61 g (20.6 mmol)6-Bromo-3-iodo-8-(methylsulfanyl)imidazo[1,2-a]pyrazine which wasprepared according to Intermediate Example 2, supra, 5.48 g[4-(cyclopropylcarbamoyl)phenyl]boronic acid, 1.68 gdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethaneadduct, 13.1 g tripotassium tetraoxophosphate was dissolved in 65 mLtetrahydrofuran and 35 mL water and stirred at 40° C. for 16 hours. Mostof the solvent was removed under reduced pressure and the residueextracted with ethyl acetate. The organic phase was washed with brineand dried over sodium sulfate. After filtration and removal of solventthe residue was subjected to a column chromatography on silica gel togive 4.88 g (59%) of the title compound along with starting material.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.92 (2H), 2.70 (3H), 2.95 (1H), 6.32 (1H),7.60 (2H), 7.77 (1H), 7.92 (2H), 8.07 (1H) ppm.

Example 2N-Cyclopropyl-4-[8-(methylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide)

A mixture of 0.64 g (1.59 mmol)4-[6-Bromo-8-(methylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamidewhich was prepared according to example 1, 387 mg phenylboronic acid, 23mL n-propanol, 4.5 mL 1-methyl-2pyrrolidone, 2.4 mL of an aqueous 2Mpotassium carbonate solution, 20.8 mg triphenylphosphine, and 111 mgbis(triphenylphosphine)palladium was stirred at 120° C. for 2 hours. Thesolution was cooled, water added, and extracted with dichloromethane.The organic phase was dried over sodium sulfate. After filtration andremoval of solvent the residue was subjected to a column chromatographyon silica gel to give 520 g (82%) of the title compound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.93 (2H), 2.81 (3H), 2.96 (1H), 6.32 (1H),7.37-7.51 (3H), 7.66 (2H), 7.78 (1H), 7.91-7.98 (4H), 8.31 (1H) ppm.

Example 3N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide(compound Example 3A) and(RS)—N-cyclopropyl-4-[8-(methylsulfinyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide(compound Example 3B)

To a suspension of 610 mg (1.52 mmol)N-Cyclopropyl-4-[8-(methylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 2 and 10 mL dichloromethane wereadded 864 mg 3-chlorobenzenecarboperoxoic acid in portions and themixture was stirred for an additional hour at 23° C. The solvent wasremoved, ethyl acetate and methanol were added and the organic phase waswashed with water, aqueous sodium thiosulfate, sodium hydrogencarbonatesolution and dried over sodium sulfate. After filtration and removal ofsolvent the residue was subjected to a column chromatography on silicagel to give 475 mg (72%) of the title compound Example 3A and 64 mg(10%) of the title compound Example 3B.

¹H-NMR (CDCl₃) of 3A: δ=0.69 (2H), 0.94 (2H), 2.97 (1H), 3.64 (3H), 6.37(1H), 7.42-7.54 (3H), 7.68 (2H), 7.89 (2H), 7.99 (2H), 8.09 (1H), 8.70(1H) ppm.

¹H-NMR (CDCl₃) of 3B: δ=0.67 (2H), 0.90 (2H), 2.94 (1H), 3.23 (3H), 6.74(1H), 7.38-7.49 (3H), 7.65 (2H), 7.92 (1H), 7.96 (2H), 7.98 (2H), 8.60(1H) ppm.

Example 4N-Cyclopropyl-4-[8-(ethylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide

To a solution of 40 mg (92 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 in 1.6 mL tetrahydrofuran wereadded 29 mg sodium ethanethiolate and the mixture was stirred at 23° C.for 16 hours. Water was added, the mixture extracted withdichloromethane and the organic phase dried over sodium sulfate. Afterfiltration and removal of solvent the residue was subjected to achromatography on silica gel plates to give 28.5 mg (71%) of the titlecompound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.92 (2H), 1.53 (3H), 2.95 (1H), 3.46 (2H),6.42 (1H), 7.38-7.49 (3H), 7.65 (2H), 7.76 (1H), 7.92 (2H), 7.94 (2H),8.29 (1H) ppm.

Example 5 (RS)N-Cyclopropyl-4-[8-(ethylsulfinyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide(compound Example 5A) andN-Cyclopropyl-4-[8-(ethylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide(compound Example 5B)

A solution of 17.5 mg (42 μmol)N-Cyclopropyl-4-[8-(ethylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 4 in 2.0 mL dichloromethane wascooled to −30° C. and 0.42 mL of a 0.15 molar dimethyldioxirane solutionin acetone were added. After 15 minutes of stirring the mixture waswarmed to 23° C., the solvent removed and the residue was purified bychromatography on silica gel plates to give 13.6 mg (47%) of titlecompound Example 5A and 8.6 mg (29%) of title compound Example 5B.

¹H-NMR (CDCl₃) of 5A: δ=0.70 (2H), 0.92 (2H), 1.44 (3H), 2.97 (1H), 3.46(1H), 3.56 (1H), 6.61 (1H), 7.38-7.50 (3H), 7.64 (2H), 7.90 (1H), 7.96(2H), 7.99 (2H), 8.57 (1H) ppm.

¹H-NMR (CDCl₃) of 5B: δ=0.69 (2H), 0.93 (2H), 1.55 (3H), 2.96 (1H), 3.89(2H), 6.46 (1H), 7.42-7.53 (4H), 7.65 (2H), 7.89 (2H), 7.99 (2H), 8.06(1H) ppm.

Example 6N-Cyclopropyl-4-[6-phenyl-8-(propylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]benzamide

40 mg (92 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 were transformed in analogy toexample 4 using sodium propane-1-thiolate to give after working up andpurification 27.4 mg (66%) of the title compound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.92 (2H), 1.13 (3H), 1.91 (2H), 2.95 (1H),3.43 (2H), 6.44 (1H), 7.36-7.51 (3H), 7.64 (2H), 7.76 (1H), 7.91 (2H),7.94 (2H), 8.29 (1H) ppm.

Example 7 (RS)N-Cyclopropyl-4-[6-phenyl-8-(propylsulfinyl)imidazo[1,2-a]pyrazin-3-yl]benzamide(compound Example 7A) andN-Cyclopropyl-4-[6-phenyl-8-(propylsulfonyl)imidazo[1,2-a]pyrazin-3-yl]benzamide(compound Example 7B)

23.4 mg (55 μmol)N-Cyclopropyl-4-[6-phenyl-8-(propylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 6 were transformed in analogy toexample 5 to give after purification 13.2 mg (52%) of title compoundExample 7A and 7.9 mg (31%) of title compound Example 7B.

¹H-NMR (CDCl₃) of 7A: δ=0.69 (2H), 0.91 (2H), 1.13 (3H), 1.88 (1H), 2.05(1H), 2.97 (1H), 3.33-3.51 (2H), 6.69 (1H), 7.38-7.49 (3H), 7.61 (2H),7.89 (1H), 7.95 (2H), 7.99 (2H), 8.56 (1H) ppm.

¹H-NMR (CDCl₃) of 7B: δ=0.69 (2H), 0.93 (2H), 1.14 (3H), 2.05 (2H), 2.97(1H), 3.83 (2H), 6.39 (1H), 7.43-7.53 (3H), 7.67 (2H), 7.90 (2H), 7.99(2H), 8.07 (1H), 8.69 (1H) ppm.

Example 84-[8-(Butylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamide

40 mg (92 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 were transformed in analogy toexample 4 using sodium butane-1-thiolate to give after working up andpurification 25.6 mg (59%) of the title compound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.92 (2H), 0.99 (3H), 1.57 (2H), 1.87 (2H),2.95 (1H), 3.46 (2H), 6.38 (1H), 7.37-7.51 (3H), 7.65 (2H), 7.77 (1H),7.89-7.97 (4H), 8.29 (1H) ppm.

Example 9 (RS)4-[8-(Butylsulfinyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamide(compound Example 9A) and4-[8-(Butylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamide(compound Example 9B)

21.3 mg (48 μmol)4-[8-(Butylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamidewhich was prepared according to example 8 were transformed in analogy toexample 5 to give after purification 11.8 mg (51%) of title compoundExample 9A and 6.5 mg (27%) of title compound Example 9B.

¹H-NMR (CDCl₃) of 9A: δ=0.69 (2H), 0.90 (2H), 0.95 (3H), 1.54 (2H), 1.81(1H), 1.99 (1H), 2.97 (1H), 3.40 (1H), 3.50 (1H), 6.66 (1H), 7.39-7.49(3H), 7.63 (2H), 7.90 (1H), 7.95 (2H), 7.98 (2H), 8.56 (1H) ppm.

¹H-NMR (CDCl₃) of 9B: δ=0.69 (2H), 0.92 (2H), 0.97 (3H), 1.54 (2H), 1.98(2H), 2.96 (1H), 3.85 (2H), 6.40 (1H), 7.43-7.53 (3H), 7.66 (2H), 7.90(2H), 7.98 (2H), 8.07 (1H), 8.69 (1H) ppm.

Example 10N-Cyclopropyl-4-{8-[(3,3-dimethylbutyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide

40 mg (92 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 were transformed in analogy toexample 4 using sodium 2,2-dimethylpropane-1-thiolate to give afterworking up and purification 16.0 mg (35%) of the title compound.

¹H-NMR (CDCl₃): δ=0.66 (2H), 0.89 (2H), 1.01 (9H), 1.75 (2H), 2.92 (1H),3.40 (2H), 7.36-7.48 (3H), 7.63 (2H), 6.68 (1H), 7.73 (1H), 7.89-7.96(4H), 8.28 (1H) ppm.

Example 11 (RS)N-Cyclopropyl-4-{8-[(3,3-dimethylbutyl)sulfinyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide(compound Example 11A) andN-Cyclopropyl-4-{8-[(3,3-dimethylbutyl)sulfonyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide(compound Example 11B)

12.5 mg (27 μmol)N-Cyclopropyl-4-{8-[(3,3-dimethylbutyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamidewhich was prepared according to example 10 were transformed in analogyto example 5 to give after purification 4.9 mg (36%) of title compound11A and 5.5 mg (39%) of title compound 11B.

¹H-NMR (CDCl₃) of 11A: δ=0.69 (2H), 0.88-0.97 (11H), 1.70 (1H), 1.88(1H), 2.97 (1H), 3.41 (1H), 3.53 (1H), 6.48 (1H), 7.41-7.51 (3H), 7.67(2H), 7.93 (1H), 7.98 (4H), 8.60 (1H) ppm.

¹H-NMR (CDCl₃) of 11B: δ=0.68 (2H), 0.93 (2H), 0.96 (9H), 1.86 (2H),2.97 (1H), 3.86 (2H), 6.41 (1H), 7.43-7.53 (3H), 7.67 (2H), 7.90 (2H),7.99 (2H), 8.07 (1H), 8.70 (1H) ppm.

Example 12 (RS)N-Cyclopropyl-4-{6-phenyl-8-[(tetrahydrofuran-2-ylmethyl)sulfanyl]imidazo[1,2-a]pyrazin-3-yl}benzamide

40 mg (92 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 were transformed in analogy toexample 4 using (RS) sodium tetrahydrofuran-2-ylmethanethiolate to giveafter working up and purification 31.6 mg (69%) of the title compound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.92 (2H), 1.76-2.06 (3H), 2.13 (1H), 2.95(1H), 3.54 (1H), 3.76-3.87 (2H), 3.98 (1H), 4.35 (1H), 6.42 (1H),7.36-7.52 (3H), 7.64 (2H), 7.77 (1H), 7.91 (2H), 7.94 (2H), 8.30 (1H)ppm.

Example 13 (RS)N-cyclopropyl-4-{6-phenyl-8-[(2RS)-(tetrahydrofuran-2-ylmethyl)sulfinyl]imidazo[1,2-a]pyrazin-3-yl}benzamide(compound Example 13A) and (RS)N-cyclopropyl-4-{6-phenyl-8-[(tetrahydrofuran-2-ylmethyl)sulfonyl]imidazo[1,2-a]pyrazin-3-yl}benzamide(compound Example 13B)

26.6 mg (57 μmol) (RS)N-Cyclopropyl-4-{6-phenyl-8-[(tetrahydrofuran-2-ylmethyl)sulfanyl]imidazo[1,2-a]pyrazin-3-yl}benzamidewhich was prepared according to example 12 were transformed in analogyto example 5 to give after purification 10.9 mg (38%) of title compound13A and 10.2 mg (34%) of title compound 13B.

¹H-NMR (CDCl₃) of 13A: δ=0.69 (2H), 0.92 (2H), 1.72 (1H), 1.97 (2H),2.18 (1H), 2.96 (1H), 3.44-4.03 (4H), 4.46+4.58 (1H), 6.61+6.63 (1H),7.39-7.49 (3H), 7.62+7.64 (2H), 7.89+7.90 (1H), 7.95 (2H), 7.98 (2H),8.56 (1H) ppm.

¹H-NMR (CDCl₃) of 13B: δ=0.69 (2H), 0.92 (2H), 1.79-1.98 (3H), 2.22(1H), 2.96 (1H), 3.61 (2H), 3.79 (1H), 4.44 (1H), 4.56 (1H), 6.48 (1H),7.40-7.51 (3H), 7.65 (2H), 7.91 (2H), 7.98 (2H), 8.03 (1H), 8.67 (1H)ppm.

Example 144-[6-bromo-8-(methylsulfonyl)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamide

480 mg (1.19 mmol)4-[6-Bromo-8-(methylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamidewhich was prepared according to example 1 were transformed in analogy toexample 3 to give after working up and purification 325 mg (60%) of thetitle compound.

¹H-NMR (DMSO-d6): δ=0.57 (2H), 0.69 (2H), 2.86 (1H), 3.62 (3H), 7.85(2H), 7.99 (2H), 8.34 (1H), 8.56 (1H), 9.06 (1H) ppm.

Example 15 (RS)N-cyclopropyl-4-{8-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide

To a solution of 114 mg (274 μmol)(RS)—N-cyclopropyl-4-[8-(methylsulfinyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 in 3 mL dichloromethane wereadded 68 mg 2,2,2-trifluoroacetamide, 48.5 mg oxomagnesium, and 145 mgdiacetoxy(phenyl)-13-iodane. After the mixture was stirred at 23° C. for5 minutes, 12.1 mg rhodium(II)diacetate were added and stirringcontinued for 15 hours. Again, 12.1 mg rhodium(II)diacetate were addedand stirring continued for additional 24 hours. After filtration thesolvent was removed and the residue was purified by chromatography onsilica gel plates to give 22.8 mg (16%) of the title compound along withstarting material.

¹H-NMR (CDCl₃): δ=0.68 (2H), 0.93 (2H), 2.96 (1H), 3.93 (3H), 6.36 (1H),7.44-7.54 (3H), 7.69 (2H), 7.88 (2H), 8.00 (2H), 8.08 (1H), 8.74 (1H)ppm.

Example 16 tert-butyl[2-({3-[4-(cyclopropylcarbamoyl)phenyl]-6-phenylimidazo[1,2-a]pyrazin-8-yl}sulfanyl)ethyl]carbamate

234 μL tert-butyl (2-sulfanylethyl)carbamate were added to a suspensionof 55.5 mg sodium hydride (60% in white oil) in 2.5 mL tetrahydrofuranat 23° C. After 5 minutes of stirring, a solution of 100 mg (231 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 in 1.5 mL tetrahydrofuranewere added and stirring was continued for four hours. Water was addedand the mixture extracted with dichloromethane and dried over sodiumsulfate. After filtration and solvent removal the residue was purifiedby chromatography to give 87.3 mg (71%) of the title compound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.92 (2H), 1.41 (9H), 2.96 (1H), 3.61 (4H),5.21 (1H), 6.35 (1H), 7.37-7.52 (3H), 7.65 (2H), 7.79 (1H), 7.90 (2H),7.94 (2H), 8.31 (1H) ppm.

Example 17N-cyclopropyl-4-[8-(pentylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide

50 mg (116 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 were transformed in analogy toexample 4 using sodium pentane-1-thiolate to give after working up andpurification 32 mg (61%) of the title compound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.86-0.98 (5H), 1.40 (2H), 1.53 (2H), 1.88(2H), 2.95 (1H), 3.44 (2H), 6.40 (1H), 7.35-7.51 (3H), 7.65 (2H), 7.76(1H), 7.91 (2H), 7.94 (2H), 8.29 (1H) ppm.

Example 18 (RS)N-cyclopropyl-4-[8-(pentylsulfinyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide(compound Example 18A) andN-cyclopropyl-4-[8-(pentylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide(compound Example 18B)

26.8 mg (59 μmol)N-cyclopropyl-4-[8-(pentylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 17 were transformed in analogyto example 5 to give after purification 0.4 mg (1%) of title compoundExample 18A and 23 mg (77%) of title compound Example 18B.

¹H-NMR (CDCl₃) of 18A: δ=0.68 (2H), 0.90 (3H), 0.93 (2H), 1.32-1.55(4H), 1.86 (1H), 2.04 (1H), 2.97 (1H), 3.41 (1H), 3.50 (1H), 6.32 (1H),7.42-7.52 (3H), 7.70 (2H), 7.95 (1H), 7.98 (2H), 8.01 (2H), 8.61 (1H)ppm.

¹H-NMR (CDCl₃) of 18B: δ=0.69 (2H), 0.90 (3H), 0.92 (2H), 1.29-1.55(4H), 2.00 (2H), 2.96 (1H), 3.84 (2H), 6.47 (1H), 7.41-7.52 (3H), 7.64(2H), 7.88 (2H), 7.99 (2H), 8.05 (1H), 8.68 (1H) ppm.

Example 19N-cyclopropyl-4-[8-(isopropylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide

50 mg (116 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 were transformed in analogy toexample 4 using sodium propane-2-thiolate to give after working up andpurification 32 mg (64%) of the title compound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.92 (2H), 1.58 (6H), 2.95 (1H), 4.38 (1H),6.40 (1H), 7.36-7.51 (3H), 7.65 (2H), 7.76 (1H), 7.91 (2H), 7.94 (2H),8.29 (1H) ppm.

Example 20 (RS)N-cyclopropyl-4-[8-(isopropylsulfinyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide(compound Example 20A) andN-cyclopropyl-4-[8-(isopropylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide(compound Example 20B)

29.7 mg (69 μmol)N-cyclopropyl-4-[8-(isopropylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 19 were transformed in analogyto example 5 to give after purification 1.6 mg (5%) of title compoundExample 20A and 23.8 mg (71%) of title compound Example 20B.

¹H-NMR (CDCl₃) of 20A: δ=0.69 (2H), 0.94 (2H), 1.31 (3H), 1.51 (3H),2.97 (1H), 3.93 (1H), 6.38 (1H), 7.41-7.52 (3H), 7.69 (2H), 7.94 (1H),7.98 (2H), 8.00 (2H), 8.60 (1H) ppm.

¹H-NMR (CDCl₃) of 20B: δ=0.69 (2H), 0.92 (2H), 1.52 (6H), 2.96 (1H),4.44 (1H), 6.47 (1H), 7.40-7.51 (3H), 7.64 (2H), 7.90 (2H), 7.99 (2H),8.03 (1H), 8.68 (1H) ppm.

Example 21N-cyclopropyl-4-[8-(isobutylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide

50 mg (116 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 were transformed in analogy toexample 4 using sodium 2-methylpropane-1-thiolate to give after workingup and purification 38 mg (74%) of the title compound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.91 (2H), 1.13 (6H), 2.15 (1H), 2.95 (1H),3.36 (2H), 6.45 (1H), 7.36-7.51 (3H), 7.64 (2H), 7.76 (1H), 7.91 (2H),7.94 (2H), 8.28 (1H) ppm.

Example 22 (RS)N-cyclopropyl-4-[8-(isobutylsulfinyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide(compound Example 22A) andN-cyclopropyl-4-[8-(isobutylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide(compound Example 22B)

35.2 mg (80 μmol)N-cyclopropyl-4-[8-(isobutylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 21 were transformed in analogyto example 5 to give after purification 2.8 mg (8%) of title compoundExample 22A and 26.1 mg (66%) of title compound Example 22B.

¹H-NMR (CDCl₃) of 22A: δ=0.69 (2H), 0.94 (2H), 1.14 (3H), 1.32 (3H),2.50 (1H), 2.97 (1H), 3.26-3.34 (2H), 6.42 (1H), 7.41-7.51 (3H), 7.67(2H), 7.94 (1H), 7.96-8.01 (4H), 8.59 (1H) ppm.

¹H-NMR (CDCl₃) of 22B: δ=0.69 (2H), 0.92 (2H), 1.18 (6H), 2.54 (1H),2.96 (1H), 3.75 (2H), 6.51 (1H), 7.39-7.51 (3H), 7.63 (2H), 7.88 (2H),7.98 (2H), 8.03 (1H), 8.66 (1H) ppm.

Example 23N-cyclopropyl-4-{8-[(3-methylbutyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide

50 mg (116 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 were transformed in analogy toexample 4 using sodium 3-methylbutane-1-thiolate to give after workingup and purification 36 mg (68%) of the title compound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.92 (2H), 1.00 (6H), 1.72-1.93 (3H), 2.95(1H), 3.45 (2H), 6.41 (1H), 7.36-7.50 (3H), 7.65 (2H), 7.76 (1H),7.88-7.98 (4H), 8.29 (1H) ppm.

Example 24 (RS)N-cyclopropyl-4-{8-[(3-methylbutyl)sulfinyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide(compound Example 24A) andN-cyclopropyl-4-{8-[(3-methylbutyl)sulfonyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide(compound Example 24B)

30.4 mg (67 μmol)N-cyclopropyl-4-{8-[(3-methylbutyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamidewhich was prepared according to example 23 were transformed in analogyto example 5 to give after purification 5.0 mg (15%) of title compoundExample 24A and 22.9 mg (67%) of title compound Example 24B.

¹H-NMR (CDCl₃) of 24A: δ=0.69 (2H), 0.89-1.00 (8H), 1.66-1.83 (2H), 1.92(1H), 2.97 (1H), 3.41 (1H), 3.53 (1H), 6.48 (1H), 7.39-7.51 (3H), 7.66(2H), 7.92 (1H), 7.98 (4H), 8.59 (1H) ppm.

¹H-NMR (CDCl₃) of 24B: δ=0.69 (2H), 0.93 (2H), 0.96 (6H), 1.78 (1H),1.87 (2H), 2.96 (1H), 3.85 (2H), 6.45 (1H), 7.41-7.52 (3H), 7.65 (2H),7.89 (2H), 7.99 (2H), 8.06 (1H), 8.69 (1H) ppm.

Example 25N-cyclopropyl-4-{6-phenyl-8-[(2,2,2-trifluoroethyl)sulfanyl]imidazo[1,2-a]pyrazin-3-yl}benzamide

50 mg (116 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 were transformed in analogy toexample 4 using sodium 2,2,2-trifluoroethanethiolate to give afterworking up and purification 19 mg (35%) of the title compound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.93 (2H), 2.96 (1H), 4.27 (2H), 6.33 (1H),7.39-7.53 (3H), 7.67 (2H), 7.84 (1H), 7.87 (2H), 7.95 (2H), 8.35 (1H)ppm.

Example 26 (RS)N-cyclopropyl-4-{6-phenyl-8-[(2,2,2-trifluoroethyl)sulfinyl]imidazo[1,2-a]pyrazin-3-yl}benzamide(compound Example 26A) andN-cyclopropyl-4-{6-phenyl-8-[(2,2,2-trifluoroethyl)sulfonyl]imidazo[1,2-a]pyrazin-3-yl}benzamide(compound Example 26B)

7.2 mg (37 μmol)N-cyclopropyl-4-{6-phenyl-8-[(2,2,2-trifluoroethyl)sulfanyl]imidazo[1,2-a]pyrazin-3-yl}benzamidewhich was prepared according to example 25 were transformed in analogyto example 5 to give after purification 5.4 mg (29%) of title compoundExample 26A and 4.3 mg (22%) of title compound Example 26B.

¹H-NMR (CDCl₃) of 26A: δ=0.64 (2H), 0.87 (2H), 2.90 (1H), 4.07 (1H),4.51 (1H), 7.06 (1H), 7.38-7.50 (3H), 7.66 (2H), 7.90-8.01 (5H), 8.65(1H) ppm.

¹H-NMR (CDCl₃) of 26B: δ=0.68 (2H), 0.94 (2H), 2.97 (1H), 4.88 (2H),6.35 (1H), 7.43-7.54 (3H), 7.69 (2H), 7.90 (2H), 8.00 (2H), 8.10 (1H),8.73 (1H) ppm.

Example 27N-cyclopropyl-4-{8-[(2-furylmethyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide

50 mg (116 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 were transformed in analogy toexample 4 using sodium 2-furylmethanethiolate to give after working upand purification 34 mg (63%) of the title compound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.91 (2H), 2.95 (1H), 4.75 (2H), 6.28 (1H),6.33 (1H), 6.44 (1H), 7.35 (1H), 7.37-7.51 (3H), 7.63 (2H), 7.76 (1H),7.94 (4H), 8.31 (1H) ppm.

Example 28 (RS)N-cyclopropyl-4-{8-[(2-furylmethyl)sulfinyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide(compound Example 28A) andN-cyclopropyl-4-{8-[(2-furylmethyl)sulfonyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide(compound Example 28B)

mg (62 μmol)N-cyclopropyl-4-{8-[(2-furylmethyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamidewhich was prepared according to example 27 were transformed in analogyto example 5 to give after purification 5.1 mg (16%) of title compoundExample 28A and 18.8 mg (58%) of title compound Example 28B.

¹H-NMR (CDCl₃) of 28A: δ=0.68 (2H), 0.93 (2H), 2.96 (1H), 4.72 (1H),4.90 (1H), 6.30 (1H), 6.40 (1H), 6.43 (1H), 7.38-7.51 (4H), 7.69 (2H),7.89-8.04 (5H), 8.60 (1H) ppm.

¹H-NMR (CDCl₃) of 28B: δ=0.69 (2H), 0.93 (2H), 2.96 (1H), 5.27 (2H),6.31 (1H), 6.43 (1H), 6.45 (1H), 7.34 (1H), 7.40-7.51 (3H), 7.66 (2H),7.90 (2H), 7.99 (2H), 8.07 (1H), 8.69 (1H) ppm.

Example 293-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)-6-phenylimidazo[1,2-a]pyrazine

80 mg (188 μmol)6-bromo-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)imidazo[1,2-a]pyrazinewhich was prepared according to example 29a were transformed in analogyto example 2 to give after after working up and purification 40.0 mg(50%) of the title compound.

¹H-NMR (DMSO-d6): δ=0.91-0.99 (4H), 2.02 (1H), 2.71 (3H), 3.91 (1H),7.39 (1H), 7.46 (2H), 7.62 (1H), 7.76 (2H), 7.88 (2H), 7.89 (1H), 8.08(2H), 8.60 (1H) ppm.

Example 29a6-bromo-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)imidazo[1,2-a]pyrazine

1.0 g (2.70 mmol)6-Bromo-3-iodo-8-(methylsulfanyl)imidazo[1,2-a]pyrazine which wasprepared according to example 1a were transformed in analogy to example1 using2-cyclopropyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-imidazoleto give after working up and purification 575 mg (50%) of the titlecompound.

Example 303-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)-6-(4-vinylphenyl)imidazo[1,2-a]pyrazine

200 mg (469 μmol)6-bromo-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)imidazo[1,2-a]pyrazinewhich was prepared according to example 29a were transformed in analogyto example 2 using (4-vinylphenyl)boronic acid to give after working upand purification 171 mg (81%) of the title compound.

¹H-NMR (CDCl₃): δ=0.97-1.10 (4H), 2.02 (1H), 2.80 (3H), 5.30 (1H), 5.81(1H), 6.76 (1H), 7.28 (1H), 7.49 (2H), 7.57 (2H), 7.74 (1H), 7.85-7.97(4H), 8.35 (1H), 9.46 (1H) ppm.

Example 313-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)-6-(pyridin-4-yl)imidazo[1,2-a]pyrazine

80 mg (188 μmol)6-bromo-3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)imidazo[1,2-a]pyrazinewhich was prepared according to example 29a were transformed in analogyto example 2 using pyridin-4-ylboronic acid to give after working up andpurification 49.3 mg (62%) of the title compound.

¹H-NMR (CDCl₃): δ=0.99-1.09 (4H), 2.02 (1H), 2.81 (3H), 7.29 (1H), 7.56(2H), 7.78 (1H), 7.87 (2H), 7.92 (2H), 8.47 (1H), 8.70 (2H) ppm.

Example 323-{3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-[(methylsulfanyl)imidazo[1,2-a]pyrazin-6-yl}prop-2-yn-1-ol

To a solution of 80 mg (188 μmol)6-bromo-3,4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)imidazo[1,2-a]pyrazinewhich was prepared according to example 29a in 5.6 mL tetrahydrofuranwere added 232 μL piperidine, 131 mg prop-2-yn-1-ol and 54 mgtetrakis(triphenylphosphine)palladium. The mixture was stirred at 80° C.for 2 hours. The solution was cooled, water added, and extracted withdichloromethane. The organic phase was dried over sodium sulfate. Afterfiltration and removal of solvent the residue was subjected to a columnchromatography on silica gel to give 51.8 mg (28%) of the titlecompound.

¹H-NMR (CDCl₃): δ=0.98 (4H), 2.00 (1H), 2.65 (3H), 4.44 (2H), 7.17 (1H),7.43 (2H), 7.67 (1H), 7.74 (2H), 8.10 (1H) ppm.

Example 33N-[2-({3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-6-phenylimidazo[1,2-a]pyrazin-8-yl}sulfanyl)ethyl]acetamide

50 mg (116 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 were transformed in analogy toexample 4 using sodium 2-acetamidoethanethiolate to give after workingup and purification 29.5 mg (54%) of the title compound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.92 (2H), 1.81 (3H), 2.95 (1H), 3.64 (2H),3.74 (2H), 6.38 (1H), 6.46 (1H), 7.39-7.54 (3H), 7.65 (2H), 7.80 (1H),7.88 (2H), 7.94 (2H), 8.32 (1H) ppm.

Example 342-(4-{3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)imidazo[1,2-a]pyrazin-6-yl}phenyl)ethanol(compound Example 34A), (1R or1S)-1-(4-{3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)imidazo[1,2-a]pyrazin-6-yl}phenyl)ethanol(compound Example 34B) and (1S or1R)-1-(4-{3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)imidazo[1,2-a]pyrazin-6-yl}phenyl)ethanol(compound Example 34C)

To a solution of 100 mg (0.22 mmol)3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)-6-(4-vinylphenyl)imidazo[1,2-a]pyrazinewhich was prepared according to example 30 in 4.0 mL tetrahydrofuranwere added 0.89 mL of a 1.0 M solution of boran-tetrahydrofuran complexin tetrahydrofuran and the mixture was stirred for 2 hours at 23° C.After cooling to 3° C. 0.68 mL sodium hydroxide solution (5% in water)was added followed after 5 minutes by 0.17 mL of hydrogen peroxide (30%in water). The mixture was allowed to warm to 23° C. and stirring wascontinued for 2 hours. Water was added and the mixture was extractedwith ethyl acetate. The organic phase was washed with sodiumthiosulfate, brine and dried over sodium sulfate. After filtration andremoval of solvent the residue was purified by chromatography on achiral phase to give 10.2 mg (9%) of the title compound Example 34A, 1.8mg (1.6%) of the title compound Example 34B, and 1.5 mg (1.4%) of thetitle compound Example 34C.

¹H-NMR (CDCl₃) of 34A: δ=0.91-0.98 (4H), 1.97 (1H), 2.71 (3H), 2.83(2H), 3.77 (2H), 7.15 (1H), 7.24 (2H), 7.48 (2H), 7.61 (1H), 7.76 (2H),7.80 (2H), 8.24 (1H) ppm.

¹H-NMR (CDCl₃) of 34B and 34C: δ=0.96-1.02 (4H), 1.48 (3H), 2.00 (1H),2.76 (3H), 4.90 (1H), 7.20 (1H), 7.43 (2H), 7.53 (2H), 7.68 (1H), 7.81(2H), 7.90 (2H), 8.31 (1H) ppm.

Example 35N-cyclopropyl-4-{8-[(4-hydroxybutyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide

50 mg (116 μmol)N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamidewhich was prepared according to example 3 were transformed in analogy toexample 16 using 4-sulfanylbutan-1-ol to give after working up andpurification 24 mg (45%) of the title compound.

¹H-NMR (CDCl₃): δ=0.67 (2H), 0.92 (2H), 1.68 (1H), 1.82 (2H), 1.98 (2H),2.95 (1H), 3.49 (2H), 3.73 (2H), 6.41 (1H), 7.36-7.50 (3H), 7.64 (2H),7.76 (1H), 7.90 (2H), 7.93 (2H), 8.28 (1H) ppm.

Example 36N-cyclopropyl-4-{8-[(4-hydroxybutyl)sulfonyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide

22.5 mg (49 μmol)N-cyclopropyl-4-{8-[(4-hydroxybutyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamidewhich was prepared according to example 35 were transformed in analogyto example 5 to give after purification 17.2 mg (68%) of the titlecompound.

¹H-NMR (CDCl₃): δ=0.69 (2H), 0.91 (2H), 1.77 (2H), 1.96 (1H), 2.08 (2H),2.95 (1H), 3.70 (2H), 3.88 (2H), 6.64 (1H), 7.34-7.47 (3H), 7.61 (2H),7.84 (2H), 7.92-8.01 (3H), 8.64 (1H) ppm.

Example 374-{8-[(2-aminoethyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}-N-cyclopropylbenzamide

To a solution of 15 mg (28 μmol) tert-butyl[2-({3-[4-(cyclopropylcarbamoyl)phenyl]-6-phenylimidazo[1,2-a]pyrazin-8-yl}sulfanyl)ethyl]carbamatewhich was prepared according to example 16 in 270 μL dichloromethane wasadded 134 μL trifluoroacetic acid and the mixture was stirred at 23° C.for 45 minutes. After removal of solvent the residue was purified bychromatography give 10.7 mg (79%) of the title compound.

¹H-NMR (CD₃OD): δ=0.66 (2H), 0.83 (2H), 2.88 (1H), 3.30 (2H), 3.65 (2H),7.39 (1H), 7.46 (2H), 7.80 (2H), 7.86 (1H), 7.98 (2H), 8.01 (2H), 8.54(1H) ppm.

Example 38 (RS) tert-butyl[2-({3-[4-(cyclopropylcarbamoyl)phenyl]-6-phenylimidazo[1,2-a]pyrazin-8-yl}sulfinyl)ethyl]carbamate(compound Example 38A) and tert-butyl[2-({3-[4-(cyclopropylcarbamoyl)phenyl]-6-phenylimidazo[1,2-a]pyrazin-8-yl}sulfonyl)ethyl]carbamate(compound Example 38B)

118 mg (223 μmol) tert-butyl[2-({3-[4-(cyclopropylcarbamoyl)phenyl]-6-phenylimidazo[1,2-a]pyrazin-8-yl}sulfanyl)ethyl]carbamatewhich was prepared according to example 16 were transformed in analogyto example 5 to give after purification 45.1 mg (35%) of title compound38A and 49.0 mg (39%) of title compound 38B.

¹H-NMR (CDCl₃) of 38A: δ=0.68 (2H), 0.93 (2H), 1.33 (9H), 2.96 (1H),3.66-3.83 (4H), 5.32 (1H), 6.43 (1H), 7.40-7.52 (3H), 7.67 (2H),7.89-8.02 (5H), 8.59 (1H) ppm.

¹H-NMR (CDCl₃) of 38B: δ=0.68 (2H), 0.93 (2H), 1.36 (9H), 2.96 (1H),3.81 (2H), 4.07 (2H), 5.35 (1H), 6.38 (1H), 7.43-7.53 (3H), 7.67 (2H),7.90 (2H), 7.99 (2H), 8.08 (1H), 8.70 (1H) ppm.

Example 394-{8-[(2-aminoethyl)sulfonyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}-N-cyclopropylbenzamide

44.7 mg (80 μmol) tert-butyl[2-({3-[4-(cyclopropylcarbamoyl)phenyl]-6-phenylimidazo[1,2-a]pyrazin-8-yl}sulfonyl)ethyl]carbamatewhich was prepared according to example 38 were transformed in analogyto example 37 to give after purification 38.5 mg (99%) of title compound

¹H-NMR (DMSO-d6): δ=0.61 (2H), 0.73 (2H), 2.90 (1H), 3.38 (2H), 4.26(2H), 7.48 (1H), 7.54 (2H), 7.95 (2H), 7.99-8.13 (6H), 8.34 (1H), 8.60(1H), 9.19 (1H) ppm.

Further, the compounds of formula (I) of the present invention can beconverted to any salt as described herein, by any method which is knownto the person skilled in the art. Similarly, any salt of a compound offormula (I) of the present invention can be converted into the freecompound, by any method which is known to the person skilled in the art.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilised to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions that are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound, or salt thereof, of the present invention. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is preferably that amount which produces a result or exerts aninfluence on the particular condition being treated. The compounds ofthe present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatin,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, coloring agents, and flavoring agents such as peppermint, oil ofwintergreen, or cherry flavoring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavoring and coloring agentsdescribed above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methycellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimise or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al., “Compendium of Excipients forParenteral Formulations” PDA Journal of Pharmaceutical Science aTechnology 1998, 52(5), 238-311; Strickley, R. G “ParenteralFormulations of Small Molecule Therapeutics Marketed in the UnitedStates (1999)-Part-1” PDA Journal of Pharmaceutical Science a Technology1999, 53(6), 324-349; and Nema, S. et al., “Excipients and Their Use inInjectable Products” PDA Journal of Pharmaceutical Science a Technology1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);

adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);

aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)

air displacement agents (examples include but are not limited tonitrogen and argon);

antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);

antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);

antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);

binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);

buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate)

carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection)

chelating agents (examples include but are not limited to edetatedisodium and edetic acid)

colorants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);

clarifying agents (examples include but are not limited to bentonite);emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate)

flavorants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);

levigating agents (examples include but are not limited to mineral oiland glycerin);

oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);

ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);

penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono- or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas)

plasticizers (examples include but are not limited to diethyl phthalateand glycerol);

solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);

stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);

suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));

surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);

suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);

sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);

tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);

tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);

tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);

tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);

tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);

tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);

tablet/capsule opaquants (examples include but are not limited totitanium dioxide);

tablet polishing agents (examples include but are not limited to carnubawax and white wax);

thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);

tonicity agents (examples include but are not limited to dextrose andsodium chloride);

viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);and

wetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of thisinvention can be made using sterile, injectable water, and the pH isadjusted if necessary. The solution is diluted for administration to 1-2mg/mL with sterile 5% dextrose and is administered as an IV infusionover about 60 minutes.

Lyophilised powder for IV administration: A sterile preparation can beprepared with (i) 100-1000 mg of the desired compound of this inventionas a lyophilised powder, (ii) 32-327 mg/mL sodium citrate, and (iii)300-3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15-60minutes.

Intramuscular suspension: The following solution or suspension can beprepared, for intramuscular injection:

50 mg/mL of the desired, water-insoluble compound of this invention

5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride

9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active ingredient.The capsules are washed and dried. The active ingredient can bedissolved in a mixture of polyethylene glycol, glycerin and sorbitol toprepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit is 100 mg of active ingredient, 0.2mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Combination Therapies

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. The present invention relates also to suchcombinations. For example, the compounds of this invention can becombined with known anti-hyper-proliferative or other indication agents,and the like, as well as with admixtures and combinations thereof. Otherindication agents include, but are not limited to, anti-angiogenicagents, mitotic inhibitors, alkylating agents, anti-metabolites,DNA-intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzyme inhibitors, toposisomerase inhibitors, biologicalresponse modifiers, or anti-hormones.

The additional pharmaceutical agent can be afinitor, aldesleukin,alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi,altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine,anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin,5-azacytidine, azathioprine, BAY 80-6946, BAY 108-2439, BCG or tice BCG,bestatin, betamethasone acetate, betamethasone sodium phosphate,bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan,calcitonin, campath, capecitabine, carboplatin, casodex, cefesone,celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine,cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, DaunoXome, decadron, decadron phosphate, delestrogen,denileukin diftitox, depo-medrol, deslorelin, dexrazoxane,diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin,dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin,epoetin alfa, epogen, eptaplatin, ergamisol, estrace, estradiol,estramustine phosphate sodium, ethinyl estradiol, ethyol, etidronicacid, etopophos, etoposide, fadrozole, farston, filgrastim, finasteride,fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridinemonophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide,formestane, fosteabine, fotemustine, fulvestrant, gammagard,gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCl,histrelin, hycamtin, hydrocortone, eyrthro-hydroxynonyladenine,hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferonalpha, interferon-alpha 2, interferon alfa-2A, interferon alfa-2B,interferon alfa-n1, interferon alfa-n3, interferon beta, interferongamma-1a, interleukin-2, intron A, iressa, irinotecan, kytril, lentinansulfate, letrozole, leucovorin, leuprolide, leuprolide acetate,levamisole, levofolinic acid calcium salt, levothroid, levoxyl,lomustine, lonidamine, marinol, mechlorethamine, mecobalamin,medroxyprogesterone acetate, megestrol acetate, melphalan, menest,6-mercaptopurine, Mesna, methotrexate, metvix, miltefosine, minocycline,mitomycin C, mitotane, mitoxantrone, Modrenal, Myocet, nedaplatin,neulasta, neumega, neupogen, nilutamide, nolvadex, NSC-631570, OCT-43,octreotide, ondansetron HCl, orapred, oxaliplatin, paclitaxel,pediapred, pegaspargase, Pegasys, pentostatin, picibanil, pilocarpineHCl, pirarubicin, plicamycin, porfimer sodium, prednimustine,prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed,RDEA 119, rebif, rhenium-186 etidronate, rituximab, roferon-A,romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran,sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy,streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin,tasonermin, tastolactone, taxotere, teceleukin, temozolomide,teniposide, testosterone propionate, testred, thioguanine, thiotepa,thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab,trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine,trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine,valrubicin, vesnarinone, vinblastine, vincristine, vindesine,vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran,ABI-007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene,asoprisnil, atamestane, atrasentan, sorafenib (BAY 43-9006), avastin,CCl-779, CDC-501, celebrex, cetuximab, crisnatol, cyproterone acetate,decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin,eflornithine, exatecan, fenretinide, histamine dihydrochloride,histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid,interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin,L-651582, lanreotide, lapatinib, lasofoxifene, libra, lonafarnib,miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin,nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem,paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21, quazepam,R-1549, raloxifene, ranpirnase, 13-cis -retinoic acid, satraplatin,seocalcitol, sunitinib, T-138067, tarceva, taxoprexin, thymosin alpha 1,tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene,TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin,vinflunine, Z-100, zoledronic acid or combinations thereof.

Optional anti-hyper-proliferative agents which can be added to thecomposition include but are not limited to compounds listed on thecancer chemotherapy drug regimens in the 11^(th) Edition of the MerckIndex, (1996), which is hereby incorporated by reference, such asasparaginase, bleomycin, carboplatin, carmustine, chlorambucil,cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin,epothilone, an epothilone derivative, etoposide, 5-fluorouracil,hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin,lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate,mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine,raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine,vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment of neoplasticdiseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated byreference, such as aminoglutethimide, L-asparaginase, azathioprine,5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemonophosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethylmelamine, uridine, and vinorelbine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to otheranti-cancer agents such as epothilone and its derivatives, irinotecan,raloxifen and topotecan.

The compounds of the invention may also be administered in combinationwith protein therapeutics. Such protein therapeutics suitable for thetreatment of cancer or other angiogenic disorders and for use with thecompositions of the invention include, but are not limited to, aninterferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonisticmonoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin,anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab,trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1,bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab,rhMBL, MFE-CP1+ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35,MT-103, rinfabate, AS-1402, B43-genistein, L-19 basedradioimmunotherapeutics, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322,rhCC10, r(m)CRP, MORAb-009, aviscumine, MDX-1307, Her-2 vaccine,APC-8024, NGR-hTNF, rhH1.3, IGN-311, Endostatin, volociximab, PRO-1762,lexatumumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein,PRX-321, CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab,alpha-particle-emitting radioisotope-llinked lintuzumab, EM-1421,HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPV-16-E7,Javelin—prostate cancer, Javelin—melanoma, NY-ESO-1 vaccine, EGFvaccine, CYT-004-MelQbG10, WT1 peptide, oregovomab, ofatumumab,zalutumumab, cintredekin besudotox, WX-G250, Albuferon, aflibercept,denosumab, vaccine, CTP-37, efungumab, or 131I-chTNT-1/B. Monoclonalantibodies useful as the protein therapeutic include, but are notlimited to, muromonab-CD3, abciximab, edrecolomab, daclizumab,gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab,efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab,daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.

The compounds of the invention may also be combined with biologicaltherapeutic agents, such as antibodies (e.g. avastin, rituxan, erbitux,herceptin), or recombinant proteins.

The compounds of the invention may also be in combination withantiangiogenesis agents, such as, for example, with avastin, axitinib,DAST, recentin, sorafenib or sunitinib. Combinations with inhibitors ofproteasomes or mTOR inhibitors, or anti-hormones or steroidal metabolicenzyme inhibitors are also possible.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

-   (1) yield better efficacy in reducing the growth of a tumor or even    eliminate the tumor as compared to administration of either agent    alone,-   (2) provide for the administration of lesser amounts of the    administered chemotherapeutic agents,-   (3) provide for a chemotherapeutic treatment that is well tolerated    in the patient with fewer deleterious pharmacological complications    than observed with single agent chemotherapies and certain other    combined therapies,-   (4) provide for treating a broader spectrum of different cancer    types in mammals, especially humans,-   (5) provide for a higher response rate among treated patients,-   (6) provide for a longer survival time among treated patients    compared to standard chemotherapy treatments,-   (7) provide a longer time for tumor progression, and/or-   (8) yield efficacy and tolerability results at least as good as    those of the agents used alone, compared to known instances where    other cancer agent combinations produce antagonistic effects.

Methods of Sensitizing Cells to Radiation

In a distinct embodiment of the present invention, a compound of thepresent invention may be used to sensitize a cell to radiation. That is,treatment of a cell with a compound of the present invention prior toradiation treatment of the cell renders the cell more susceptible to DNAdamage and cell death than the cell would be in the absence of anytreatment with a compound of the invention. In one aspect, the cell istreated with at least one compound of the invention.

Thus, the present invention also provides a method of killing a cell,wherein a cell is administered one or more compounds of the invention incombination with conventional radiation therapy.

The present invention also provides a method of rendering a cell moresusceptible to cell death, wherein the cell is treated one or morecompounds of the invention prior to the treatment of the cell to causeor induce cell death. In one aspect, after the cell is treated with oneor more compounds of the invention, the cell is treated with at leastone compound, or at least one method, or a combination thereof, in orderto cause DNA damage for the purpose of inhibiting the function of thenormal cell or killing the cell.

In one embodiment, a cell is killed by treating the cell with at leastone DNA damaging agent. That is, after treating a cell with one or morecompounds of the invention to sensitize the cell to cell death, the cellis treated with at least one DNA damaging agent to kill the cell. DNAdamaging agents useful in the present invention include, but are notlimited to, chemotherapeutic agents (e.g., cisplatinum), ionizingradiation (X-rays, ultraviolet radiation), carcinogenic agents, andmutagenic agents.

In another embodiment, a cell is killed by treating the cell with atleast one method to cause or induce DNA damage. Such methods include,but are not limited to, activation of a cell signalling pathway thatresults in DNA damage when the pathway is activated, inhibiting of acell signalling pathway that results in DNA damage when the pathway isinhibited, and inducing a biochemical change in a cell, wherein thechange results in DNA damage. By way of a non-limiting example, a DNArepair pathway in a cell can be inhibited, thereby preventing the repairof DNA damage and resulting in an abnormal accumulation of DNA damage ina cell.

In one aspect of the invention, a compound of the invention isadministered to a cell prior to the radiation or orther induction of DNAdamage in the cell. In another aspect of the invention, a compound ofthe invention is administered to a cell concomitantly with the radiationor orther induction of DNA damage in the cell. In yet another aspect ofthe invention, a compound of the invention is administered to a cellimmediately after radiation or orther induction of DNA damage in thecell has begun.

In another aspect, the cell is in vitro. In another embodiment, the cellis in vivo.

As mentioned supra, the compounds of the present invention havesurprisingly been found to effectively inhibit Mps-1 and may thereforebe used for the treatment or prophylaxis of diseases of uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses, ordiseases which are accompanied with uncontrolled cell growth,proliferation and/or survival, inappropriate cellular immune responses,or inappropriate cellular inflammatory responses, particularly in whichthe uncontrolled cell growth, proliferation and/or survival,inappropriate cellular immune responses, or inappropriate cellularinflammatory responses is mediated by Mps-1, such as, for example,haematological tumours, solid tumours, and/or metastases thereof, e.g.leukaemias and myelodysplastic syndrome, malignant lymphomas, head andneck tumours including brain tumours and brain metastases, tumours ofthe thorax including non-small cell and small cell lung tumours,gastrointestinal tumours, endocrine tumours, mammary and othergynaecological tumours, urological tumours including renal, bladder andprostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

In accordance with another aspect therefore, the present inventioncovers a compound of general formula (I), or a stereoisomer, a tautomer,an N-oxide, a hydrate, a solvate, or a salt thereof, particularly apharmaceutically acceptable salt thereof, or a mixture of same, asdescribed and defined herein, for use in the treatment or prophylaxis ofa disease, as mentioned supra.

Another particular aspect of the present invention is therefore the useof a compound of general formula (I), described supra, or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, particularly a pharmaceutically acceptable salt thereof, or amixture of same, for the prophylaxis or treatment of a disease.

Another particular aspect of the present invention is therefore the useof a compound of general formula (I) described supra for manufacturing apharmaceutical composition for the treatment or prophylaxis of adisease.

The diseases referred to in the two preceding paragraphs are diseases ofuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses, or diseases which are accompanied with uncontrolled cellgrowth, proliferation and/or survival, inappropriate cellular immuneresponses, or inappropriate cellular inflammatory responses,particularly in which the uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses is mediated by Mps-1, such as, forexample, haematological tumours, solid tumours, and/or metastasesthereof, e.g. leukaemias and myelodysplastic syndrome, malignantlymphomas, head and neck tumours including brain tumours and brainmetastases, tumours of the thorax including non-small cell and smallcell lung tumours, gastrointestinal tumours, endocrine tumours, mammaryand other gynaecological tumours, urological tumours including renal,bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

The term “inappropriate” within the context of the present invention, inparticular in the context of “inappropriate cellular immune responses,or inappropriate cellular inflammatory responses”, as used herein, is tobe understood as preferably meaning a response which is less than, orgreater than normal, and which is associated with, responsible for, orresults in, the pathology of said diseases.

Preferably, the use is in the treatment or prophylaxis of diseases,wherein the diseases are haemotological tumours, solid tumours and/ormetastases thereof.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalianhyper-proliferative disorders. Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce apoptosis. This method comprises administering to amammal in need thereof, including a human, an amount of a compound ofthis invention, or a pharmaceutically acceptable salt, isomer,polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which iseffective to treat the disorder. Hyper-proliferative disorders includebut are not limited, e.g., psoriasis, keloids, and other hyperplasiasaffecting the skin, benign prostate hyperplasia (BPH), solid tumors,such as cancers of the breast, respiratory tract, brain, reproductiveorgans, digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginal,and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell. Lymphomas include, but are not limitedto AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of thecentral nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Methods of Treating Kinase Disorders

The present invention also provides methods for the treatment ofdisorders associated with aberrant mitogen extracellular kinaseactivity, including, but not limited to stroke, heart failure,hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cysticfibrosis, symptoms of xenograft rejections, septic shock or asthma.

Effective amounts of compounds of the present invention can be used totreat such disorders, including those diseases (e.g., cancer) mentionedin the Background section above. Nonetheless, such cancers and otherdiseases can be treated with compounds of the present invention,regardless of the mechanism of action and/or the relationship betweenthe kinase and the disorder.

The phrase “aberrant kinase activity” or “aberrant tyrosine kinaseactivity,” includes any abnormal expression or activity of the geneencoding the kinase or of the polypeptide it encodes. Examples of suchaberrant activity, include, but are not limited to, over-expression ofthe gene or polypeptide; gene amplification ; mutations which produceconstitutively-active or hyperactive kinase activity ; gene mutations,deletions, substitutions, additions, etc.

The present invention also provides for methods of inhibiting a kinaseactivity, especially of mitogen extracellular kinase, comprisingadministering an effective amount of a compound of the presentinvention, including salts, polymorphs, metabolites, hydrates, solvates,prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof.Kinase activity can be inhibited in cells (e.g., in vitro), or in thecells of a mammalian subject, especially a human patient in need oftreatment.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity [Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD ;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855],neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumor enlargement and metastasis. Moreover, thegrowth of new blood and lymph vessels in a tumor provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation ;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death or apoptosis of such cell types.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders and angiogenicdisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Preferably, the diseases of said method are haematological tumours,solid tumour and/or metastases thereof.

The compounds of the present invention can be used in particular intherapy and prevention, i.e. prophylaxis, of tumour growth andmetastases, especially in solid tumours of all indications and stageswith or without pre-treatment of the tumour growth.

Methods of testing for a particular pharmacological or pharmaceuticalproperty are well known to persons skilled in the art.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

Biological Assay: Proliferation Assay

Cultivated tumor cells (MCF7, hormone dependent human mammary carcinomacells, ATCC HTB22; NCI-H460, human non-small cell lung carcinoma cells,ATCC HTB-177; DU 145, hormone-independent human prostate carcinomacells, ATCC HTB-81; HeLa-MaTu, human cervical carcinoma cells, EPO-GmbH,Berlin; HeLa-MaTu-ADR, multidrug-resistant human cervical carcinomacells, EPO-GmbH, Berlin; HeLa human cervical tumor cells, ATCC CCL-2;B16F10 mouse melanoma cells, ATCC CRL-6475) were plated at a density of5000 cells/well (MCF7, DU145, HeLa-MaTu-ADR), 3000 cells/well (NCI-H460,HeLa-MaTu, HeLa), or 1000 cells/well (B16F10) in a 96-well multititerplate in 200 μl of their respective growth medium supplemented 10% fetalcalf serum. After 24 hours, the cells of one plate (zero-point plate)were stained with crystal violet (see below), while the medium of theother plates was replaced by fresh culture medium (200 μl), to which thetest substances were added in various concentrations (0 μM, as well asin the range of 0.01-30 μM; the final concentration of the solventdimethyl sulfoxide was 0.5%). The cells were incubated for 4 days in thepresence of test substances. Cell proliferation was determined bystaining the cells with crystal violet: the cells were fixed by adding20 μl/measuring point of an 11% glutaric aldehyde solution for 15minutes at room temperature. After three washing cycles of the fixedcells with water, the plates were dried at room temperature. The cellswere stained by adding 100 μl/measuring point of a 0.1% crystal violetsolution (pH 3.0). After three washing cycles of the stained cells withwater, the plates were dried at room temperature. The dye was dissolvedby adding 100 μl/measuring point of a 10% acetic acid solution. Theextinction was determined by photometry at a wavelength of 595 nm. Thechange of cell number, in percent, was calculated by normalization ofthe measured values to the extinction values of the zero-point plate(=0%) and the extinction of the untreated (0 μm) cells (=100%). The IC50values were determined by means of a 4 parameter fit using the company'sown software.

Mps-1 Kinase Assay

The human kinase Mps-1 phosphorylates a biotinylated substrate peptide.Detection of the phosphorylated product is achieved by time-resolvedfluorescence resonance energy transfer (TR-FRET) from Europium-labelledanti-phospho-Serine/Threonine antibody as donor to streptavidin labelledwith cross-linked allophycocyanin (SA-XLent) as acceptor. Compounds aretested for their inhibition of the kinase activity.

N-terminally GST-tagged human full length recombinant Mps-1 kinase(purchased from Invitrogen, Karslruhe, Germany, cat. no PV4071) wasused. As substrate for the kinase reaction a biotinylated peptide of theamino-acid sequence PWDPDDADITEILG (C-terminus in amide form, purchasedfrom Biosynthan GmbH, Berlin) was used.

For the assay 50 nl of a 100-fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of asolution of Mps-1 in assay buffer [0.1 mM sodium-ortho-vanadate, 10 mMMgCl₂, 2 mM DTT, 25 mM Hepes pH 7.7, 0.05% BSA, 0.001% Pluronic F-127]were added and the mixture was incubated for 15 min at 22° C. to allowpre-binding of the test compounds to Mps-1 before the start of thekinase reaction. Then the kinase reaction was started by the addition of3 μl of a solution of 16.7 adenosine-tri-phosphate (ATP, 16.7 μM=>finalconc. in the 5 μl assay volume is 10 μM) and peptide substrate (1.67μM=>final conc. in the 5 μl assay volume is 1 μM) in assay buffer andthe resulting mixture was incubated for a reaction time of 60 min at 22°C. The concentration of Mps-1 in the assay was adjusted to the activityof the enzyme lot and was chosen appropriate to have the assay in thelinear range, typical enzyme concentrations were in the range of about 1nM (final conc. in the 5 μl assay volume). The reaction was stopped bythe addition of 3 μl of a solution of HTRF detection reagents (100 mMHepes pH 7.4, 0.1% BSA, 40 mM EDTA, 140 nM Streptavidin-XLent[#61GSTXLB, Fa. Cis Biointernational, Marcoule, France], 1.5 nManti-phospho(Ser/Thr)-Europium-antibody [#AD0180, PerkinElmer LAS,Rodgau-Jügesheim, Germany].

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the phosphorylated peptide to theanti-phospho(Ser/Thr)-Europium-antibody. Subsequently the amount ofphosphorylated substrate was evaluated by measurement of the resonanceenergy transfer from the Europium-labelled anti-phospho(Ser/Thr)antibody to the Streptavidin-XLent. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a Viewlux TR-FRET reader (PerkinElmer LAS, Rodgau-Jügesheim,Germany). The “blank-corrected normalized ratio” (a Viewlux specificreadout, similar to the traditional ratio of the emissions at 665 nm andat 622 nm, in which blank and Eu-donor crosstalk are subtracted from the665 nm signal before the ratio is calculated) was taken as the measurefor the amount of phosphorylated substrate. The data were normalised(enzyme reaction without inhibitor=0% inhibition, all other assaycomponents but no enzyme=100% inhibition). Test compounds were tested onthe same microtiter plate at 10 different concentrations in the range of20 μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM,9.2 nM, 3.1 nM and 1 nM, dilution series prepared before the assay atthe level of the 100 fold conc. stock solutions by serial 1:3 dilutions)in duplicate values for each concentration and IC₅₀ values werecalculated by a 4 parameter fit using an inhouse software.

TABLE Example Mps1 IC50 [nM]  1 607.0  2 25.7  3A 6.0  3B 8.9  4 22.2 5A 27.7  5B 7.7  6 11.0  7A 20.0  7B 10.1  8 26.3  9A 10.3  9B 14.0 1085.1 11A 23.0 11B 4.3 12 8.0 13A NT 13B 7.8 14 NT 15 5.2 16 67.6 17 79.818B 7.5 19 22.3 20B 13.9 21 13.2 22A 12.7 22B 6.4 23 25.2 24A 14.5 24B6.5 25 26.3 26A 6.2 26B 8.1 27 40.8 28A 16.9 28B 7.1 29 544.0 30 3100.031 125.0 32 151.0 33 19.9 34A 48.7 34B 58.2 34C 95 35 3.7 36 5.1 In theabove Table, NT = not tested

Spindle Assembly Checkpoint Assay

The spindle assembly checkpoint assures the proper segregation ofchromosomes during mitosis. Upon entry into mitosis, chromosomes beginto condensate which is accompanied by the phosphorylation of histone H3on serine 10. Dephosphorylation of histone H3 on serine 10 begins inanaphase and ends at early telophase. Accordingly, phosphorylation ofhistone H3 on serine 10 can be utilized as a marker of cells in mitosis.Nocodazole is a microtubule destabilizing substance. Thus, nocodazoleinterferes with microtubule dynamics and mobilises the spindle assemblycheckpoint. The cells arrest in mitosis at G2/M transition and exhibitphosphorylated histone H3 on serine 10. An inhibition of the spindleassembly checkpoint by Mps-1 inhibitors overrides the mitotic blockagein the presence of nocodazole, and the cells complete mitosisprematurely. This alteration is detected by the decrease of cells withphosphorylation of histone H3 on serine 10. This decline is used as amarker to determine the capability of compounds of the present inventionto induce a mitotic breakthrough.

Cultivated cells of the human cervical tumor cell line HeLa (ATCC CCL-2)were plated at a density of 2500 cells/well in a 384-well microtiterplate in 20 μl Dulbeco's Medium (w/o phenol red, w/o sodium pyruvate, w1000 mg/ml glucose, w pyridoxine) supplemented with 1% (v/v) glutamine,1% (v/v) penicillin, 1% (v/v) streptomycin and 10% (v/v) fetal calfserum. After incubation overnight at 37° C., 10 μl/well nocodazole at afinal concentration of 0.1 μg/ml were added to cells. After 24 hincubation, cells were arrested at G2/M phase of the cell cycleprogression. Test compounds solubilised in dimethyl sulfoxide (DMSO)were added at various concentrations (0 μM, as well as in the range of0.005 μM -10 μM; the final concentration of the solvent DMSO was 0.5%(v/v)). Cells were incubated for 4 h at 37° C. in the presence of testcompounds. Thereafter, cells were fixed in 4% (v/v) paraformaldehyde inphosphate buffered saline (PBS) at 4° C. overnight then permeabilised in0.1% (v/v) Triton X™ 100 in PBS at room temperature for 20 min andblocked in 0.5% (v/v) bovine serum albumin (BSA) in PBS at roomtemperature for 15 min. After washing with PBS, 20 μl/well antibodysolution (anti-phospho-histone H3 clone 3H10, FITC; Upstate, Cat#16-222;1:200 dilution) was added to cells, which were incubated for 2 h at roomtemperature. Afterwards, cells were washed with PBS and 20 μl/wellHOECHST 33342 dye solution (5 μg/ml) was added to cells and cells wereincubated 12 min at room temperature in the dark. Cells were washedtwice with PBS then covered with PBS and stored at 4° C. until analysis.Images were acquired with a Perkin Elmer OPERA™ High-Content Analysisreader. Images were analyzed with image analysis software MetaXpress™from Molecular devices utilizing the Cell Cycle application module. Inthis assay both labels HOECHST 33342 and phosphorylated Histone H3 onserine 10 were measured. HOECHST 33342 labels DNA and is used to countcell number. The staining of phosphorylated Histone H3 on serine 10determines the number of mitotic cells. Inhibition of Mps-1 decreasesthe number of mitotic cells in the presence of nocodazole indicating aninappropriate mitotic progression. The raw assay data were furtheranalysed by four parameter logistic regression analysis to determine theIC₅₀ value for each tested compound.

It will be apparent to persons skilled in the art that assays for otherMps kinases may be performed in analogy using the appropriate reagents.

Thus the compounds of the present invention effectively inhibit one ormore Mps-1 kinases and are therefore suitable for the treatment orprophylaxis of diseases of uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses, particularly in which theuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses is mediated by Mps-1, more particularly in which the diseasesof uncontrolled cell growth, proliferation and/or survival,inappropriate cellular immune responses, or inappropriate cellularinflammatory responses are haemotological tumours, solid tumours and/ormetastases thereof, e.g. leukaemias and myelodysplastic syndrome,malignant lymphomas, head and neck tumours including brain tumours andbrain metastases, tumours of the thorax including non-small cell andsmall cell lung tumours, gastrointestinal tumours, endocrine tumours,mammary and other gynaecological tumours, urological tumours includingrenal, bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

1. A compound of formula (I):

in which: X represents an —SRS, —S(═O)R⁵, —S(═O)₂R⁵,—S(═O)(═NR^(5a))R^(5b), or —S(═O)₂N(R^(5b))R^(5c) group; R¹ represents ahydrogen atom or a halogen atom, or a —CN, C₁-C₆ alkyl, haloC₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-,—C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,—C(═O)R⁸, —C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶,—N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b),—N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),—N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸, —N(R^(8a))C(═O)OR^(8b),—N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸,—NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸, —O(C═O)R⁸,—O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,—S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b),or —S(═O)(═NR^(8a))R^(8b) group; R² represents a hydrogen atom or ahalogen atom, or a —CN, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₂-C₆-alkenyl-, or C₂-C₆-alkynyl-, —C(═O)R⁸,—C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶, —N(R^(8a))R^(8b), —NO₂,—N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂,—N(H)C(═O)N(H)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),—N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸, —N(R^(8a))C(═O)OR^(8b),—N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸,—NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸, —O(C═O)R⁸,—O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,—S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b),or —S(═O)(═NR^(8a))R^(8b) group; or a group selected from:

R^(3a), R^(3b) represent, independently from one another, a hydrogenatom or a halogen atom, or a —CN, C₁-C₆-alkyl-,—(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to 7-memberedheterocycloalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-,—C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, C₁-C₆-alkyl-aryl-, heteroaryl, —C(═O)R⁸, —C(═O)N(H)R⁸,—C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶, —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸,—N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b),—N(H)C(═O)N(R^(8a))R^(8b), —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸,—N(R^(8a))C(═O)OR^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),—N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸,—O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸,—S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸,—S(═O)₂N(R^(8a))R^(8b), or —S(═O)(═NR^(8a))R^(8b) group; saidC₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, heteroaryl-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-,a 3- to 7-membered heterocycloalkyl, C₂-C₆-alkenyl-,C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-, C₁-C₆-alkyl-aryl-,heteroaryl, being optionally substituted, identically or differently,with 1, 2, 3, or 4 R⁷ groups; R^(4a), R^(4b), R^(4c), R^(4d) represent,independently from each other, a hydrogen or halogen atom, or a —CN,halo-C₁-C₆-alkyl-, R^(8a)(R^(8b))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, —C(═O)R⁸,—C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁸, —N(R^(8a))R^(8b), —NO₂,—N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),—N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸, —N(R^(8a))C(═O)OR^(8b),—N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸,—NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸, —O(C═O)R⁸,—O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,—S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b),—S(═O)(═NR^(8a))R^(8b) group; or R^(4c), together with R², forms an*N(R⁶)—N═C*—NH₂ group; R⁵, R^(5b), R^(5c), represent, independently fromeach other, a hydrogen atom, or a C₁-C₆-alkyl-,—(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to 7-memberedheterocycloalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-,—C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, heteroaryl group; said C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,—(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to7-membered heterocycloalkyl), aryl-C₁-C₆-alkyl-,heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-,HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, heteroaryl, being optionally substituted, identically ordifferently, with 1, 2, 3, or 4 R⁷ groups; R^(5a) represents a hydrogenatom or a —C(═O)—C₁-C₆-alkyl, or —C(═O)—C₃-C₆-cycloalkyl group; saidC₁-C₆-alkyl being optionally substituted, identically or differently,with one or more halogen atom; R⁶, R^(6a) represent, independently fromeach other, a hydrogen atom or a C₁-C₆-alkyl or C₃-C₆-cycloalkyl group,R⁷ represents a hydrogen or halogen atom, or a —CN, halo-C₁-C₆-alkyl-,R^(8a)(R^(8b))N—C₁-C₆-alkyl-, H0-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₂-C₆-alkenyl, —C(═O)R⁸, —C(═O)N(H)R⁸,—C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁸, —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸,—N(R^(8a))C(═O)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),—N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸, —N(R^(8a))C(═O)OR^(8b),—N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸,—NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸, —O(C═O)R⁸,—O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,—S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b),—S(═O)(═NR^(8a))R^(8b) group; R⁸, R^(8a), R^(8b), represent,independently from each other, a hydrogen atom, or a C₁-C₆-alkyl,C₃-C₆-cycloalkyl, 3- to 7-membered heterocycloalkyl, aryl, heteroaryl,aryl-C₁-C₆-alkyl-, or heteroaryl-C₁-C₆-alkyl- group; m is an integer of1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 ; or a stereoisomer, a tautomer, anN-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.2. The compound according to claim 1, wherein: X represents an —SRS,—S(═O)R⁵, —S(═O)₂R⁵, —S(═O)(═NR^(5a))R^(5b), or —S(═O)₂N(R^(5b))R^(5c)group; R¹ represents a hydrogen atom or a halogen atom, or a —CN,C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-,HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN, —C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b),—C(═O)O—R⁶, or —N(R^(8a))R^(8b) group; R² represents a —C(═O)N(H)R⁸,—C(═O)N(R^(8a))R^(8b), —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b),—N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),—N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),—N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b) group; or a group selected from:

R^(3a), R^(3b) represent, independently from one another, a hydrogenatom or a halogen atom, or a —CN, C₁-C₆-alkyl-,—(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to 7-memberedheterocycloalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-,—C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, C₁-C₆-alkyl-aryl-, heteroaryl, —C(═O)R⁸, —C(═O)N(H)R⁸,—C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶, —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸,—N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b),—N(H)C(═O)N(R^(8a))R^(8b), —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸,—N(R^(8a))C(═O)OR^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),—N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸,—O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸,—S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸,—S(═O)₂N(R^(8a))R^(8b), or —S(═O)(═NR^(8a))R^(8b) group; saidC₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,C₃-C₆-cycloalkyl-, a 3- to 7-membered heterocycloalkyl, C₂-C₆-alkenyl-,C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-, C₁-C₆-alkyl-aryl-,heteroaryl, being optionally substituted, identically or differently,with 1, 2, 3, or 4 R⁷ groups; R^(4a), R^(4b), R^(4c), R^(4d) represent,independently from each other, a hydrogen or halogen atom, or a —CN,halo-C₁-C₆-alkyl-, R^(8a)(R^(8b))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, —C(═O)R⁸,—C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁸, —N(R^(8a))R^(8b), —NO₂,—N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),—N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸, —N(R^(8a))C(═O)OR^(8b),—N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b), —N(H)S(═O)₂R⁸,—NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸, —O(C═O)R⁸,—O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸,—S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b),—S(═O)(═NR^(8a))R^(8b) group; or R^(4c), together with R², forms an*N(R⁶)—N═C*—NH₂ group; R⁵, R^(5b), R^(5c), represent, independently fromeach other, a hydrogen atom, or a C₁-C₆-alkyl-,—(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to 7-memberedheterocycloalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-,—C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, heteroaryl group; said C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,—(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to7-membered heterocycloalkyl), aryl-C₁-C₆-alkyl-,heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-,HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, heteroaryl, being optionally substituted, identically ordifferently, with 1, 2, 3, or 4 R⁷ groups, ; R^(5a) represents ahydrogen atom or a —C(═O)—C₁-C₆-alkyl, or —C(═O)—C₃-C₆-cycloalkyl group;said C₁-C₆-alkyl being optionally substituted, identically ordifferently, with one or more halogen atom; R⁶, R^(6a) represent,independently from each other, a hydrogen atom or a C₁-C₆-alkyl orC₃-C₆-cycloalkyl group, R⁷ represents a hydrogen or halogen atom, or a—CN, C₂-C₆-alkenyl, —C(═O)R⁸, —C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b),—C(═O)O—R⁸, —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b),—N(R⁸)C(═O)OR^(8a), —N(H)C(═O)N(R^(8a))R^(8b),—N(R⁸)C(═O)N(R^(8a))R^(8b), —OR⁸, —O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b),—SR⁸, —S(═O)R⁸, —S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸,—S(═O)₂N(H)R⁸, —S(═O)₂N(R^(8a))R^(8b) group; R⁸, R^(8a), R^(8b),represent, independently from each other, a hydrogen atom, or aC₁-C₆-alkyl, C₃-C₆-cycloalkyl, 3- to 7-membered heterocycloalkyl, aryl,heteroaryl, aryl-C₁-C₆-alkyl-, or heteroaryl-C₁-C₆-alkyl- group; m is aninteger of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 ; or a stereoisomer, atautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or amixture of same.
 3. The compound according to claim 1, wherein: Xrepresents an —SR⁵, —S(═O)R⁵, —S(═O)₂R⁵, —S(═O)(═NR^(5a))R^(5b), or—S(═O)₂N(R^(5b))R^(5c) group; R¹ represents a hydrogen atom or a halogenatom, or a —CN, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-,R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN,—C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶ or —N(R^(8a))R^(8b)group; R² represents a —C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b),—N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂,—N(H)C(═O)N(H)R^(8b), —N(H)C(═O)N(R^(8a))R^(8b),—N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),—N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b) group; or a group selected from:

R^(3a), R^(3b) represent, independently from one another, a hydrogenatom or a halogen atom, or a —CN, C₁-C₆-alkyl-,—(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to 7-memberedheterocycloalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-, HO—C₁-C₆-alkyl-,—C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, C₁-C₆-alkyl-aryl-, heteroaryl, —C(═O)R⁸, —C(═O)N(H)R⁸,—C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁶, —N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸,—N(R^(8a))C(═O)R^(8b), —N(H)C(═O)NH₂, —N(H)C(═O)N(H)R^(8b),—N(H)C(═O)N(R^(8a))R^(8b), —N(R⁸)C(═O)N(R^(8a))R^(8b), —N(H)C(═O)OR⁸,—N(R^(8a))C(═O)OR^(8b), —N(H)S(═O)R⁸, —N(R^(8a))S(═O)R^(8b),—N(H)S(═O)₂R⁸, —NR^(8a)S(═O)₂R^(8b), —N═S(═O)(R^(8a))R^(8b), —OH, —OR⁸,—O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —O(C═O)OR⁸, —SR⁸, —S(═O)R⁸,—S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸,—S(═O)₂N(R^(8a))R^(8b), or —S(═O)(═NR^(8a))R^(8b) group; saidC₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl, —(CH₂)_(m)—C₂-C₆-alkynyl,—(CH₂)_(m)—C₃-C₆-cycloalkyl, aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-,C₃-C₆-cycloalkyl-, a 3- to 7-membered heterocycloalkyl, C₂-C₆-alkenyl-,C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-, aryl-, C₁-C₆-alkyl-aryl-,heteroaryl, being optionally substituted, identically or differently,with 1, 2, 3, or 4 R⁷ groups; R^(4a), R^(4b), R^(4c), R^(4d) represent ahydrogen atom or R^(4c), together with R², forms an *N(R⁶)—N═C*—NH₂group; R⁵, R^(5b), R^(5c), represent, independently from each other, ahydrogen atom, or a C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,—(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to7-membered heterocycloalkyl), aryl-C₁-C₆-alkyl-,heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-,HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, heteroaryl group; said C₁-C₆-alkyl-, —(CH₂)_(m)—C₂-C₆-alkenyl,—(CH₂)_(m)—C₂-C₆-alkynyl, —(CH₂)_(m)—C₃-C₆-cycloalkyl, —(CH₂)_(m)-(3- to7-membered heterocycloalkyl), aryl-C₁-C₆-alkyl-,heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, R⁶(R^(6a))N—C₁-C₆-alkyl-,HO—C₁-C₆-alkyl-, —C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-,halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, a 3- to 7-memberedheterocycloalkyl, C₂-C₆-alkenyl-, C₃-C₆-cycloalkenyl-, C₂-C₆-alkynyl-,aryl-, heteroaryl, being optionally substituted, identically ordifferently, with 1, 2, 3, or 4 R⁷ groups; R^(5a) represents a hydrogenatom or a —C(═O)—C₁-C₆-alkyl, or —C(═O)—C₃-C₆-cycloalkyl group; saidC₁-C₆-alkyl being optionally substituted, identically or differently,with one or more halogen atom; R⁶, R^(6a) represent, independently fromeach other, a hydrogen atom or a C₁-C₆-alkyl or C₃-C₆-cycloalkyl group;R⁷ represents a hydrogen or halogen atom, or a —CN, C₂-C₆-alkenyl,—C(═O)R⁸, —C(═O)N(H)R⁸, —C(═O)N(R^(8a))R^(8b), —C(═O)O—R⁸,—N(R^(8a))R^(8b), —NO₂, —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b),—N(H)C(═O)N(R^(8a))R^(8b), —N(R⁸)C(═O)N(R^(8a))R^(8b),—N(R⁸)C(═O)OR^(8a), —OR⁸, —O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b), —SR⁸,—S(═O)R⁸, —S(═O)N(H)R⁸, —S(═O)N(R^(8a))R^(8b), —S(═O₂)R⁸, —S(═O)₂N(H)R⁸,—S(═O)₂N(R^(8a))R^(8b) group; R⁸, R^(8a), R^(8b), represent,independently from each other, a hydrogen atom, or a C₁-C₆-alkyl,C₃-C₆-cycloalkyl, 3- to 7-membered heterocycloalkyl, aryl, heteroaryl,aryl-C₁-C₆-alkyl-, or heteroaryl-C₁-C₆-alkyl- group; m is an integer of1, 2 or 3; or a stereoisomer, a tautomer, an N-oxide, a hydrate, asolvate, or a salt thereof, or a mixture of same.
 4. The compoundaccording to claim 1, wherein: X represents an —SR⁵, —S(═O)R⁵,—S(═O)₂R⁵, —S(═O)(═NR^(5a))R^(5b), or —S(═O)₂N(R^(5b))R^(5c) group; R¹represents a hydrogen atom; R² represents a —C(═O)N(H)R⁸ group; or an

group; R^(3a) represents a hydrogen atom; R^(3b) represents a hydrogenatom or a halogen atom, or a C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, aryl-,C₁-C₆-alkyl-aryl-, or heteroaryl group; said C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, aryl-, C₁-C₆-alkyl-aryl- or heteroaryl, being optionallysubstituted, identically or differently, with 1, 2, 3, or 4 R⁷ groups;R^(4a), R^(4b), R^(4c), R^(4d) represent a hydrogen atom, or R^(4c),together with R², forms an *N(R⁶)—N═C*—NH₂ group; R⁵, R^(5b), R^(5c),represent, independently from each other, a C₁-C₆-alkyl-, —(CH₂)_(m)-(3-to 7-membered heterocycloalkyl), heteroaryl-C₁-C₆-alkyl-,halo-C₁-C₆-alkyl- group; said C₁-C₆-alkyl-, —(CH₂)_(m)-(3- to 7-memberedheterocycloalkyl), heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, beingoptionally substituted, identically or differently, with 1, 2, 3, or 4R⁷ groups; R^(5a) represents a hydrogen atom or a —C(═O)—C₁-C₆-alkyl, or—C(═O)—C₃-C₆-cycloalkyl group; said C₁-C₆-alkyl being optionallysubstituted, identically or differently, with one or more halogen atom;R⁶, R^(6a) represent, independently from each other, a hydrogen atom ora C₁-C₆-alkyl or C₃-C₆-cycloalkyl group; R⁷ represents a hydrogen orhalogen atom, or a halo-C₁-C₆-alkyl-, C₂-C₆-alkenyl, —C(═O)N(H)R⁸,—N(R^(8a))R^(8b), —N(H)C(═O)R⁸, —N(R^(8a))C(═O)R^(8b),—N(R⁸)C(═O)OR^(8a), —OR⁸, —O(C═O)R⁸, —O(C═O)N(R^(8a))R^(8b) group; R⁸,R^(8a), R^(8b), represent, independently from each other, a hydrogenatom, or a C₁-C₆-alkyl or C₃-C₆-cycloalkyl group; m is an integer of 1;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.
 5. The compound according to claim1, which is selected from the group consisting of:4-[6-Bromo-8-(methylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamide;N-Cyclopropyl-4-[8-(methylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide;N-Cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide;(RS)—N-cyclopropyl-4-[8-(methylsulfinyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide;N-Cyclopropyl-4-[8-(ethylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide;(RS)N-Cyclopropyl-4-[8-(ethylsulfinyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamideN-Cyclopropyl-4-[8-(ethylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide;N-Cyclopropyl-4-[6-phenyl-8-(propylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]benzamide;(RS)N-Cyclopropyl-4-[6-phenyl-8-(propylsulfinyl)imidazo[1,2-a]pyrazin-3-yl]benzamide;N-Cyclopropyl-4-[6-phenyl-8-(propylsulfonyl)imidazo[1,2-a]pyrazin-3-yl]benzamide;4-[8-(Butylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamide;(RS)4-[8-(Butylsulfinyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamide;4-[8-(Butylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamide;N-Cyclopropyl-4-{8-[(3,3-dimethylbutyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;(RS)N-Cyclopropyl-4-{8-[(3,3-dimethylbutyl)sulfinyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;N-Cyclopropyl-4-{8-[(3,3-dimethylbutyl)sulfonyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;(RS)N-Cyclopropyl-4-{6-phenyl-8-[(tetrahydrofuran-2-ylmethyl)sulfanyl]imidazo[1,2-a]pyrazin-3-yl}benzamide;(RS)N-cyclopropyl-4-{6-phenyl-8-[(2RS)-(tetrahydrofuran-2-ylmethyl)sulfinyl]imidazo[1,2-a]pyrazin-3-yl}benzamide;(RS)N-cyclopropyl-4-{6-phenyl-8-[(tetrahydrofuran-2-ylmethyl)sulfonyl]imidazo[1,2-a]pyrazin-3-yl}benzamide;4-[6-bromo-8-(methylsulfonyl)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzamide;(RS)N-cyclopropyl-4-{8-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;tert-butyl[2-({3-[4-(cyclopropylcarbamoyl)phenyl]-6-phenylimidazo[1,2-a]pyrazin-8-yl}sulfanyl)ethyl]carbamate;N-cyclopropyl-4-[8-(pentylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide;(RS)N-cyclopropyl-4-[8-(pentylsulfinyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide;N-cyclopropyl-4-[8-(pentylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide;N-cyclopropyl-4-[8-(isopropylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide;(RS)N-cyclopropyl-4-[8-(isopropylsulfinyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide;N-cyclopropyl-4-[8-(isopropylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamideN-cyclopropyl-4-[8-(isobutylsulfanyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide;(RS)N-cyclopropyl-4-[8-(isobutylsulfinyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide;N-cyclopropyl-4-{8-(isobutylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;N-cyclopropyl-4-{8-[(3-methylbutyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;(RS)N-cyclopropyl-4-{8-[(3-methylbutyl)sulfinyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;N-cyclopropyl-4-{8-[(3-methylbutyl)sulfonyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;N-cyclopropyl-4-{6-phenyl-8-[(2,2,2-trifluoroethyl)sulfanyl]imidazo[1,2-a]pyrazin-3-yl}benzamide;(RS)N-cyclopropyl-4-{6-phenyl-8-[(2,2,2-trifluoroethyl)sulfinyl]imidazo[1,2-a]pyrazin-3-yl}benzamide;N-cyclopropyl-4-{6-phenyl-8-[(2,2,2-trifluoroethyl)sulfonyl]imidazo[1,2-a]pyrazin-3-yl}benzamide;N-cyclopropyl-4-{8-[(2-furylmethyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;(RS)N-cyclopropyl-4-{8-[(2-furylmethyl)sulfinyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;N-cyclopropyl-4-{8-[(2-furylmethyl)sulfonyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)-6-phenylimidazo[1,2-a]pyrazine;3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)-6-(4-vinylphenyl)imidazo[1,2-a]pyrazine;3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)-6-(pyridin-4-yl)imidazo[1,2-a]pyrazine;3-{3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)imidazo[1,2-a]pyrazin-6-yl}prop-2-yn-1-ol;N-[2-({3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-6-phenylimidazo[1,2-a]pyrazin-8-yl}sulfanyl)ethyl]acetamide;2-(4-{3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)imidazo[1,2-a]pyrazin-6-yl}phenyl)ethanol;(1R or1S)-1-(4-{3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)imidazo[1,2-a]pyrazin-6-yl}phenyl)ethanol;(1S or1R)-1-(4-{3-[4-(2-cyclopropyl-1H-imidazol-5-yl)phenyl]-8-(methylsulfanyl)imidazo[1,2-a]pyrazin-6-yl}phenyl)ethanol;N-cyclopropyl-4-{8-[(4-hydroxybutyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;(RS)N-cyclopropyl-4-{8-[(4-hydroxybutyl)sulfinyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;N-cyclopropyl-4-{8-[(4-hydroxybutyl)sulfonyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}benzamide;4-{8-[(2-aminoethyl)sulfanyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}-N-cyclopropylbenzamide;(RS) tert-butyl[2-({3-[4-(cyclopropylcarbamoyl)phenyl]-6-phenylimidazo[1,2-a]pyrazin-8-yl}sulfinyl)ethyl]carbamate;tert-butyl[2-({3-[4-(cyclopropylcarbamoyl)phenyl]-6-phenylimidazo[1,2-a]pyrazin-8-yl}sulfonyl)ethyl]carbamate;and4-{8-[(2-aminoethyl)sulfonyl]-6-phenylimidazo[1,2-a]pyrazin-3-yl}-N-cyclopropylbenzamide.6. A method of preparing a compound of formula (Ia):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d), R^(5b)and R^(5c) are as defined in claim 1, in which method an intermediatecompound of formula (VIII):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d) are asdefined in claim 1, is allowed to react with an amine of formula(VIIIa):

in which R^(5b) and R^(5c) are as defined in claim 1, thus providing acompound of general formula (Ia).
 7. A method of preparing a compound offormula (Ib):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d), and R⁵are as defined in claim 1, in which method an intermediate methylsulphone compound of formula (VII):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d) are asdefined in claim 1, is allowed to react with a thiol of formula (VIIa),which is deprotonated:

in which R⁵ is as defined in claim 1, thus providing a compound ofgeneral formula (Ib).
 8. (canceled)
 9. A pharmaceutical compositioncomprising a compound according to claim 1 and a pharmaceuticallyacceptable diluent or carrier.
 10. A pharmaceutical combinationcomprising: one or more compounds according to claim 1; and one or moreagents selected from: a taxane, such as Docetaxel, Paclitaxel, or Taxol;an epothilone, such as Ixabepilone, Patupilone, or Sagopilone;Mitoxantrone; Predinisolone; Dexamethasone; Estramustin; Vinblastin;Vincristin; Doxorubicin; Adriamycin; Idarubicin; Daunorubicin;Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide; Procarbazine;Melphalan; 5-Fluorouracil; Capecitabine; Fludarabine; Cytarabine; Ara-C;2-Chloro-2″-deoxyadenosine; Thioguanine; an anti-androgen, such asFlutamide, Cyproterone acetate, or Bicalutamide; Bortezomib; a platinumderivative, such as Cisplatin, or Carboplatin; Chlorambucil;Methotrexate; and Rituximab.
 11. (canceled)
 12. A method for thetreatment or prophylaxis of a disease of uncontrolled cell growth,proliferation and/or survival, an inappropriate cellular immuneresponse, or an inappropriate cellular inflammatory response,particularly in which the uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune response, or inappropriatecellular inflammatory response is mediated by Mps-1, more particularlyin which the disease of uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune response, or inappropriatecellular inflammatory response is a haemotological tumour, a solidtumour and/or metastases thereof, e.g. leukaemias and myelodysplasticsyndrome, malignant lymphomas, head and neck tumours including braintumours and brain metastases, tumours of the thorax including non-smallcell and small cell lung tumours, gastrointestinal tumours, endocrinetumours, mammary and other gynaecological tumours, urological tumoursincluding renal, bladder and prostate tumours, skin tumours, andsarcomas, and/or metastases thereof comprising administering to a humanor animal in need thereof an effective amount of a compound according toclaim
 1. 13. A compound of formula (VIII):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d) are asdefined in claim 1, or a stereoisomer, a tautomer, an N-oxide, ahydrate, a solvate, or a salt thereof, or a mixture of same.
 14. Acompound of formula (VII):

in which R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(4c), R^(4d) are asdefined in claim
 1. 15. (canceled)